Orally disintegrating tablets containing rivaroxaban

Abstract

To provide rivaroxaban-containing orally disintegrating tablet having excellent dispersibility.SOLUTION: A rivaroxaban-containing orally disintegrating tablet according to the present invention is a compression molded product containing active ingredient-containing granules containing rivaroxaban as an active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture, the rapidly disintegrating granules containing an excipient and a disintegrant, and the disintegrant contained in the rapidly disintegrating granules containing either light anhydrous silicic acid or crospovidone.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an orally disintegrating tablet containing rivaroxaban that has excellent dispersibility. [Background technology]

[0002] Rivaroxaban (chemical name: 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 that inhibits factor Xa in the intrinsic and extrinsic blood coagulation cascades, thereby suppressing thrombin generation and thrombus formation (Non-Patent Document 1).

[0003] Rivaroxaban is effective when administered orally, and oral formulations thereof have been investigated. For example, Patent Document 1 discloses tablets prepared by adding additives to granules containing hydrophilized rivaroxaban and compressing the granules into tablets.

[0004] Patent Document 2 discloses a pharmaceutical composition having improved dissolution properties and excellent oral bioavailability, which is a tablet containing rivaroxaban and produced by adding a lubricant to a granulated product containing 5% by mass or less of crystalline cellulose and then compressing the granulated product.

[0005] Meanwhile, researchers of the present applicant have developed an orally disintegrating tablet that has excellent disintegration properties and reduced bitterness, which is a compression molded product containing active ingredient-containing granules, rapidly disintegrating granules, and a lubricant-containing mixture (Patent Documents 3 to 7). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2007-512274 [Patent Document 2] Japanese Patent Application Publication No. 2019-108324 [Patent Document 3] Patent No. 4551627 [Patent Document 4] Patent No. 5062871 [Patent Document 5] Patent No. 5062872 [Patent Document 6] Patent No. 5584509 [Patent Document 7] International Publication No. 2017 / 217494 Brochure [Non-patent literature]

[0007] [Non-Patent Document 1] "Xarelto (registered trademark) Tablets 10 mg Xarelto (registered trademark) Tablets 15 mg" package insert Summary of the Invention [Problem to be solved by the invention]

[0008] As described above, researchers of the applicant have developed an orally disintegrating tablet with excellent disintegration properties, and because rivaroxaban is effective when administered orally, they considered applying the structure of the orally disintegrating tablet to a rivaroxaban formulation. However, it has been found that when the orally disintegrating tablet technology developed by the researchers of the present applicant is applied to rivaroxaban formulations, the dispersibility of the resulting tablets may be poor. Therefore, an object of the present invention is to provide an orally disintegrating tablet containing rivaroxaban that has excellent dispersibility. [Means for solving the problem]

[0009] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result, have found that when an orally disintegrating tablet is obtained by mixing granules containing a medicinal ingredient including rivaroxaban, rapidly disintegrating granules, and a lubricant-containing mixture and compressing the mixture, the dispersibility of the orally disintegrating tablet can be improved by not allowing light anhydrous silicic acid and crospovidone to coexist in the rapidly disintegrating granules, thereby completing the present invention. The present invention will now be described.

[0010] [1] A compression-molded body containing active ingredient-containing granules containing rivaroxaban as the active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture, the rapidly disintegrating granules comprising an excipient and a disintegrant; An orally disintegrating tablet containing rivaroxaban, wherein the disintegrant contained in the rapidly disintegrating granules comprises either light anhydrous silicic acid or crospovidone. [2] The orally disintegrating tablet containing rivaroxaban according to [1], wherein the disintegrant contained in the rapidly disintegrating granules is only disintegrant A consisting of either light anhydrous silicic acid or crospovidone. [3] The disintegrant contained in the rapidly disintegrating granules is a disintegrant A consisting of either light anhydrous silicic acid or crospovidone; The orally disintegrating tablet containing rivaroxaban according to [1] above, which is a combination of disintegrant B consisting of one or more selected from starch, sodium starch glycolate, sodium carboxymethyl starch, carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and calcium carboxymethyl cellulose. [4] The orally disintegrating tablet containing rivaroxaban according to any one of [1] to [3], wherein the active ingredient-containing granules contain, in addition to rivaroxaban, an excipient, a disintegrant, and a binder. [5] The orally disintegrating tablet containing rivaroxaban according to any one of [1] to [4], wherein the lubricant-containing mixture contains, in addition to the lubricant, an excipient and a glidant. [6] A method for improving the dispersibility of an orally disintegrating tablet containing rivaroxaban, which is a compressed compact containing active ingredient-containing granules containing rivaroxaban as the active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture, comprising: the rapidly disintegrating granules comprising an excipient and a disintegrant; The method for producing the rapidly disintegrating granules, wherein the disintegrant contained in the rapidly disintegrating granules is either light anhydrous silicic acid or crospovidone, or a combination of a disintegrant other than light anhydrous silicic acid and crospovidone and either light anhydrous silicic acid or crospovidone. [7] A method for producing an orally disintegrating tablet containing rivaroxaban, comprising: a step of producing a medicinal ingredient-containing granule containing rivaroxaban as the medicinal ingredient; producing rapidly disintegrating granules comprising an excipient and a disintegrant, wherein the disintegrant comprises either light anhydrous silicic acid or crospovidone; A method comprising the step of mixing the active ingredient-containing granules, the rapidly disintegrating granules, and a lubricant-containing mixture and compressing the mixture. [Effects of the Invention]

[0011] The orally disintegrating tablet containing rivaroxaban according to the present invention has excellent dispersibility, and is therefore thought to rapidly disintegrate in the oral cavity, release the active ingredient rivaroxaban, and exert its effects. Therefore, the orally disintegrating tablet containing rivaroxaban according to the present invention is industrially very advantageous as one form of a preparation containing rivaroxaban as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION

[0012] The orally disintegrating tablet according to the present invention contains rivaroxaban as an active ingredient. The chemical name of rivaroxaban is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, and rivaroxaban is a selective and direct factor Xa inhibitor having the following chemical structure. It inhibits factor Xa in the intrinsic and extrinsic blood coagulation cascades, thereby suppressing thrombin production and thrombus formation. Note that rivaroxaban does not inhibit thrombin production, nor does it have a direct effect on platelets.

[0013] [ka]

[0014] The size of the raw material rivaroxaban can be adjusted appropriately. For example, the average particle diameter (D 50 ) can be 1 μm or more and 70 μm or less, and preferably 3 μm or more and 40 μm or less. Therefore, when the crystal grains of rivaroxaban are large, it is preferable to crush them in advance. In the present disclosure, the average particle diameter (D 50 ) shall be measured on a volume basis using a laser diffraction particle size distribution analyzer.

[0015] The amount and proportion of rivaroxaban in the orally disintegrating tablet of the present invention may be appropriately adjusted within a range in which rivaroxaban can exert its action and effect. For example, the amount of rivaroxaban per tablet can be 1 mg or more and 100 mg or less, preferably 2 mg or more, more preferably 5 mg or more, and preferably 50 mg or less, more preferably 20 mg or less, and even more preferably 10 mg or 15 mg. The proportion of rivaroxaban in the orally disintegrating tablet can be 1% by mass or more and 50% by mass or less, preferably 2% by mass or more, more preferably 5% by mass or more, even more preferably 10% by mass or more, and preferably 40% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less.

[0016] The rivaroxaban-containing orally disintegrating tablet according to the present invention is a compression-molded product containing active ingredient-containing granules containing rivaroxaban as the active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture.

[0017] The medicinal ingredient-containing granules may contain, in addition to the medicinal ingredient rivaroxaban, an excipient, a disintegrant, a binder, a surfactant, and the like.

[0018] An excipient is an additive that is blended to dilute a medicinal ingredient or increase the amount of the formulation to improve the formability and ease of administration of the formulation. Examples of excipients include lactose, crystalline cellulose, ethyl cellulose, starch, hydroxypropyl cellulose, mannitol, dextrin, and sucrose. The amount of excipient in the medicinal ingredient-containing granules can be adjusted as appropriate, and can be, for example, 30% by mass or more and 70% by mass or less of the total medicinal ingredient-containing granules, preferably 40% by mass or more, and preferably 60% by mass or less, and more preferably 50% by mass or less.

[0019] Disintegrants are ingredients that are incorporated to absorb moisture and promote tablet disintegration, facilitating the release of medicinal ingredients. Disintegrants are not particularly limited, and examples include croscarmellose sodium, starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose (carboxymethylcellulose), carboxymethylcellulose calcium, light anhydrous silicic acid, and crospovidone (cross-linked polyvinylpyrrolidone). The amount and proportion of disintegrant in the medicinal ingredient-containing granules may be appropriately adjusted so that the tablet disintegrates well after ingestion and the medicinal ingredients are released. For example, the amount and proportion of disintegrant may be 1% by mass or more and 20% by mass or less of the total medicinal ingredient-containing granules, preferably 2% by mass or more, more preferably 5% by mass or more, and preferably 15% by mass or less, and more preferably 10% by mass or less.

[0020] Binders are added to bind various components and increase the strength of granules or tablets. Binders are not particularly limited, and examples include hypromellose (hydroxypropyl methylcellulose), hydroxypropyl cellulose polyvinylpyrrolidone, polyvinyl alcohol, and ethyl cellulose. Hydroxypropyl cellulose is exemplified above as an excipient, but it also functions as a binder. The amount and proportion of binder in the active ingredient-containing granules may be adjusted appropriately depending on the desired granule strength or tablet strength. For example, the binder content may be 0.1% by mass or more and 10% by mass or less of the active ingredient-containing granules as a whole. The proportion is preferably 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 2% by mass or more, and is preferably 5% by mass or less, and more preferably 3% by mass or less.

[0021] Surfactants are used, for example, during the production of medicinal ingredient-containing granules to improve the affinity of low-hydrophilic components for the aqueous binder solution. In the present invention, since the medicinal ingredient rivaroxaban has relatively low hydrophilicity, it is preferable to incorporate a surfactant into the medicinal ingredient-containing granules, particularly into the aqueous binder solution during the production of the medicinal ingredient-containing granules. Examples of surfactants include anionic surfactants, cationic surfactants, nonionic surfactants, and amphoteric surfactants, with anionic surfactants such as sodium lauryl sulfate being preferred. The amount and proportion of the surfactant in the medicinal ingredient-containing granules can be adjusted appropriately depending on the production conditions of the medicinal ingredient-containing granules, and can be, for example, 0.01% by mass or more and 10% by mass or less relative to the total medicinal ingredient-containing granules. The proportion is preferably 0.1% by mass or more, more preferably 1% by mass or more, and preferably 5% by mass or less, more preferably 2% by mass or less.

[0022] The size of the granules containing the active ingredient may be adjusted as appropriate. For example, the average particle diameter (D 50 ) can be 30 μm or more and 300 μm or less, and preferably 50 μm or more and 200 μm or less.

[0023] The rapidly disintegrating granules are granules that absorb moisture in the oral cavity to rapidly promote disintegration of the orally disintegrating tablet of the present invention and accelerate the release of the active ingredient rivaroxaban. The rapidly disintegrating granules contain at least an excipient and a disintegrant.

[0024] The excipients to be blended in the rapidly disintegrating granules may be the same as those to be blended in the granules containing a medicinal ingredient, but they may be the same or different. The amount of excipient in the rapidly disintegrating granules may be adjusted appropriately, and may be, for example, 50% by mass or more and 90% by mass or less, preferably 60% by mass or more, more preferably 70% by mass or more, and more preferably 80% by mass or less, based on the total amount of the rapidly disintegrating granules.

[0025] The disintegrants contained in the rapidly disintegrating granules may be the same as those contained in the granules containing a medicinal ingredient, but they may be the same or different. However, the present inventors have found that the coexistence of light anhydrous silicic acid and crospovidone in the rapidly disintegrating granules reduces the dispersibility of the orally disintegrating tablet. Therefore, the rapidly disintegrating granules contained in the rivaroxaban-containing orally disintegrating tablet according to the present invention do not contain both light anhydrous silicic acid and crospovidone, but contain only either light anhydrous silicic acid or crospovidone. However, the disintegrants contained in the rapidly disintegrating granules may be either light anhydrous silicic acid or crospovidone alone, or they may contain a disintegrant other than light anhydrous silicic acid and crospovidone in addition to either light anhydrous silicic acid or crospovidone alone.

[0026] In the present disclosure, "dispersibility" refers to the property of the rivaroxaban-containing orally disintegrating tablet of the present invention to absorb water and disintegrate when it comes into contact with water or an aqueous solution, particularly saliva in the mouth. On the other hand, when the rapidly disintegrating granules contain both light anhydrous silicic acid and crospovidone, they do not disintegrate quickly or finely even when they absorb water, and the release rate of rivaroxaban is reduced compared to tablets in which the rapidly disintegrating granules contain only one of light anhydrous silicic acid and crospovidone but not the other.

[0027] The rapidly disintegrating granules may contain only disintegrant A consisting of either light anhydrous silicic acid or crospovidone as a disintegrant, or may contain disintegrant B other than light anhydrous silicic acid or crospovidone. Examples of disintegrant B include one or more disintegrants selected from starch, sodium starch glycolate, sodium carboxymethyl starch, carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and calcium carboxymethyl cellulose.

[0028] The amount of disintegrant in the rapidly disintegrating granules may be adjusted as appropriate, and may be, for example, 10% by mass or more and 50% by mass or less, preferably 15% by mass or more, more preferably 20% by mass or more, and preferably 40% by mass or less, more preferably 30% by mass or less, based on the total amount of the rapidly disintegrating granules.

[0029] The size of the rapidly disintegrating granules may be adjusted appropriately. For example, the average particle diameter (D 50 ) can be 30 μm or more and 200 μm or less, and preferably 40 μm or more and 150 μm or less.

[0030] The lubricant-containing mixture contains a lubricant to promote good mixing of the active ingredient-containing granules and the rapidly disintegrating granules, facilitating tableting of the mixture. The lubricant-containing mixture contains at least a lubricant and may also contain other additives such as excipients, flow agents, sweeteners, and flavors.

[0031] Lubricants are components added to adhere to the surfaces of each component to increase its fluidity or to prevent the components from adhering to the equipment. The lubricant is not particularly limited, but examples of lubricants that can be used include magnesium stearate, talc, hydrogenated vegetable oil, polyglycerol fatty acid ester, and sucrose fatty acid ester, with magnesium stearate being preferred. The amount and proportion of lubricant may be adjusted appropriately within a range that allows smooth tableting. For example, the amount may be 0.01% by mass or more and 5% by mass or less of the total tablet. The proportion is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, and preferably 2% by mass or less, and more preferably 1% by mass or less.

[0032] The excipients to be blended in the lubricant-containing mixture may be the same as those to be blended in the medicinal ingredient-containing granules, but they may be the same or different. The amount and ratio of the excipient in the lubricant-containing mixture may be adjusted as appropriate, and may be, for example, 0.1% by mass or more and 5% by mass or less relative to the entire tablet, preferably 1% by mass or more, more preferably 2% by mass or more, and preferably 4% by mass or less, and more preferably 3% by mass or less.

[0033] A glidant is a component added to enhance the fluidity of each component contained in the active ingredient-containing granules, rapidly disintegrating granules, and lubricant-containing mixture, thereby allowing them to be mixed uniformly and quickly. The glidant is not particularly limited, and examples thereof include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and talc. The amount and proportion of the glidant in the lubricant-containing mixture can be adjusted as appropriate, and may be, for example, 0.01% by mass or more and 5% by mass or less, preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and preferably 4% by mass or less, and more preferably 2% by mass or less, based on the total tablet mass.

[0034] Sweeteners are ingredients that are added to reduce the bitterness of tablet ingredients. Sweeteners are not particularly limited, but examples of sweeteners that can be used include aspartame, xylitol, erythritol, and sucrose. The amount and ratio of sweetener in the lubricant-containing mixture can be adjusted appropriately, and can be, for example, 0.1% by mass or more and 10% by mass or less of the entire tablet, preferably 0.2% by mass or more, more preferably 0.5% by mass or more, and preferably 5% by mass or less, and more preferably 2% by mass or less.

[0035] The flavoring is a component that imparts a flavor to the tablet, and the flavoring is not particularly limited, but examples thereof include yogurt flavoring, peach flavoring, grapefruit flavoring, apple flavoring, acerola flavoring, plum flavoring, plum flavoring, coffee flavoring, and black tea flavoring. The amount and ratio of the flavoring in the lubricant-containing mixture can be adjusted as appropriate, but while even a small amount of flavoring can produce a flavor, too much can make it difficult to administer. Therefore, the amount can be, for example, 0.005% by mass or more and 1% by mass or less of the entire tablet, preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and preferably 0.5% by mass or less, and more preferably 0.2% by mass or less.

[0036] The orally disintegrating tablet containing rivaroxaban according to the present invention can be produced by a general method as long as it has the above-mentioned component configuration. For example, the orally disintegrating tablet containing rivaroxaban according to the present invention can be produced by a method comprising the steps of: producing granules containing rivaroxaban as the active ingredient; producing rapidly disintegrating granules containing an excipient and a disintegrant, wherein the disintegrant contains either light anhydrous silicic acid or crospovidone; and mixing the granules containing the active ingredient, the rapidly disintegrating granules, and a mixture containing a lubricant, followed by compression molding.

[0037] The active ingredient-containing granules and the rapidly disintegrating granules can be produced according to a general granule production method, so long as the active ingredient-containing granules contain rivaroxaban as the active ingredient and the rapidly disintegrating granules contain an excipient and a specific disintegrant. For example, the granules can be produced by a wet granulation method in which a solvent is sprayed onto rolled or fluidized fine raw material powder to bind them together, or a dry granulation method in which a lubricant is blended with the raw material powder, and pressure is applied to form it into a bulk shape such as a plate, followed by pulverization and sizing. Production by a wet granulation method is preferred.

[0038] Next, the active ingredient-containing granules and the rapidly disintegrating granules are mixed with a lubricant-containing mixture, and the mixture is compressed into tablets using a tableting machine.

[0039] The water content of the rivaroxaban-containing orally disintegrating tablet of the present invention is not particularly limited, but it is preferable to adjust the manufacturing conditions of each granule so that the water content is 5% by mass or less. The water content is preferably 3% by mass or less. The lower limit of the water content is not particularly limited and may be 0% by mass, but the water content can be, for example, 0.1% by mass or more. The water content can be measured, for example, by the Karl Fischer method.

[0040] The hardness of the rivaroxaban-containing orally disintegrating tablet according to the present invention is not particularly limited, but is preferably 20 N or more and 100 N or less, for example. The hardness can be adjusted, for example, by the tableting pressure.

[0041] The size of the tablet of the present invention may be adjusted appropriately. For example, the tablet may be disc-shaped or lenticular-shaped to facilitate oral administration, with a diameter of 4 mm to 10 mm and a thickness of 2 mm to 5 mm.

[0042] The dosage of the orally disintegrating tablet containing rivaroxaban according to the present invention may be adjusted appropriately depending on the patient's symptoms, severity, age, sex, etc. For example, in terms of the dosage of rivaroxaban, 10 mg or more to 30 mg may be administered once or twice a day. In particular, for patients with a creatinine clearance of 15 mL / min or more and 29 mL / min or less, it is preferable to administer a relatively low dosage, for example, 10 mg of rivaroxaban once a day.

[0043] As mentioned above, the applicant's researchers have developed orally disintegrating tablets with excellent disintegration properties, but it has been found that when the orally disintegrating tablet technology developed by the applicant's researchers is applied to rivaroxaban formulations, the resulting tablets may have poor dispersibility. Therefore, in the present invention, in order to improve the dispersibility of rivaroxaban-containing orally disintegrating tablets, which are compression-molded products containing active ingredient-containing granules containing rivaroxaban as the active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture, the disintegrant contained in the rapidly disintegrating granules containing an excipient and a disintegrant is either light anhydrous silicic acid or crospovidone, or a combination of a disintegrant other than light anhydrous silicic acid and crospovidone with either light anhydrous silicic acid or crospovidone.

[0044] As described above, the present inventors have found that the coexistence of light anhydrous silicic acid and crospovidone in rapidly disintegrating granules reduces the dispersibility of orally disintegrating tablets. Therefore, in the present invention, the dispersibility of the tablets is improved by using the disintegrant in the rapidly disintegrating granules of rivaroxaban-containing orally disintegrating tablets as described above. [Example]

[0045] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is possible to carry out the invention by making appropriate modifications within the scope of the above and below-described aims, and all such modifications are included in the technical scope of the present invention.

[0046] Comparative Examples 1 and 2 Orally disintegrating tablets containing rivaroxaban as the active ingredient were produced by tableting a mixture of active ingredient-containing granules, rapidly disintegrating granules, and a lubricant-containing mixture having the composition shown in Table 1. In Table 1, the amount of yogurt micron is very small, so the amount of yogurt micron is not included in the "total."

[0047] [Table 1]

[0048] Specifically, rivaroxaban (active ingredient), lactose hydrate (excipient), crystalline cellulose (excipient), croscarmellose sodium (disintegrant), and a portion of hypromellose (binder) were mixed, and then stirred and granulated using a solution prepared by dissolving a portion of the hypromellose (binder) and sodium lauryl sulfate (surfactant) in purified water. The mixture was then wet-milled, dried, and sized to prepare granules containing the active ingredient. Rapidly disintegrating granules were prepared by mixing lactose hydrate (excipient), ethyl cellulose (excipient), and light anhydrous silicic acid (disintegrant) and granulating them with a dispersion of corn starch (disintegrant) and crospovidone (disintegrant) in purified water. The mixture was then dried and sized to prepare rapidly disintegrating granules. The active ingredient-containing granules, rapidly disintegrating granules, ethyl cellulose (excipient), aspartame (sweetener), light anhydrous silicic acid (flow inhibitor), and yogurt micron (flavoring) were mixed together, and then magnesium stearate (lubricant) was added, followed by tableting to obtain orally disintegrating tablets.

[0049] Test example 1: Simple dissolution test A simple dissolution test was conducted in accordance with the Japanese Pharmacopoeia, 18th Edition. Specifically, in accordance with the apparatus for the rotating basket method described in 6.10 Dissolution Test, 1.1, of the Japanese Pharmacopoeia, 18th Edition, 900 mL of purified water was added to a transparent container, and the temperature inside the container was adjusted to 37±0.5°C using a thermostatic water bath. Next, one tablet from Comparative Example 1 or Comparative Example 2 was placed on a cylindrical basket made of a mesh with openings of 0.36 to 0.44 mm, and the basket was gently immersed in purified water and left to stand for 5 minutes without rotation, after which the condition was visually confirmed. As a result, the disintegration products of all tablets containing rivaroxaban as the active ingredient were large, with 80 to 90 percent being unable to pass through the mesh and remaining on the basket, indicating poor dispersibility.

[0050] Comparative Example 3: Identifying the component causing poor dispersion The active ingredient-containing granules of Comparative Examples 1 and 2 were mixed with the disintegrants shown in Table 2 and compressed into tablets, and the resulting tablets were subjected to the simple dissolution test of Test Example 1. The results are shown in Table 2. In Table 2, "◯" indicates that the amount of disintegrated tablet material remaining on the basket was approximately 30% or less, and "×" indicates that the amount was more than approximately 30%.

[0051] [Table 2]

[0052] As shown in Table 2, it was suggested that in tablets containing rivaroxaban as the active ingredient in the active ingredient-containing granules, good dispersibility was obtained when only light anhydrous silicic acid or crospovidone was included as the rapidly disintegrating granule component, whereas the dispersibility of the tablets deteriorated when both light anhydrous silicic acid and crospovidone were included as the rapidly disintegrating granule components.

[0053] Examples 1 to 5 Orally disintegrating tablets containing rivaroxaban were produced using the composition shown in Table 3 in the same manner as in Comparative Examples 1 and 2. In Table 3, the amount of yogurt micron blended was so small that the amount of yogurt micron was not included in the "total." The dispersibility of each tablet was also tested under the conditions of Test Example 1. The results are shown in Table 3.

[0054] [Table 3]

[0055] As shown in Table 3, it was revealed that the dispersibility of orally disintegrating tablets containing rivaroxaban does not deteriorate even if light anhydrous silicic acid and crospovidone are not present in rapidly disintegrating granules that do not contain any active ingredient, even if either one is present.

[0056] Test Example 2: Dissolution test Dissolution tests were conducted in accordance with the Japanese Pharmacopoeia, 18th Edition. Specifically, a flow-through cell dissolution tester including a test solution storage tank, a solution pump, a flow-through cell, and a thermostatic water bath was used in accordance with Section 6.10, Dissolution Test Method, 1.3, of the Japanese Pharmacopoeia, 18th Edition. Approximately 5 mm diameter beads were placed in the conical lower portion of the flow-through cell, and approximately 1 mm diameter glass beads were placed on top of these. One tablet each from Comparative Examples 1 and 2 and Examples 2 to 4, which contain a fluidizer in a lubricant-containing mixture, was placed on top of the glass bead layer. A test solution adjusted to 37±0.5°C and pH 1.2 was introduced into the flow-through cell at a rate of 16 mL / min. After 120 minutes, the amount of rivaroxaban in the test solution samples was measured using a UV-visible spectrophotometer. The final cumulative dissolution rates of rivaroxaban measured in the test solution samples are shown in Table 4.

[0057] [Table 4]

[0058] As shown in Table 4, orally disintegrating tablets containing rivaroxaban as the active ingredient exhibited good dispersibility and excellent dissolution of rivaroxaban, even if light anhydrous silicic acid and crospovidone were not present in the rapidly disintegrating granules, even if either one was present.

[0059] Examples 6 and 7 Orally disintegrating tablets containing rivaroxaban having the composition shown in Table 5 were produced under the same conditions as in Comparative Examples 1 and 2. In Table 5, since the amount of yogurt micron blended was very small, the amount of yogurt micron is not included in the "total."

[0060] [Table 5]

[0061] Reference Examples 1 and 2: Production of fine granule formulations A fine granule formulation containing rivaroxaban as the active ingredient was manufactured with the composition shown in Table 6. Note that in Table 6, the amounts of sodium lauryl sulfate, aspartame, and yogurt micron are so small that the amounts of these ingredients are not included in the "total."

[0062] [Table 6]

[0063] Specifically, rivaroxaban, lactose hydrate, and hypromellose were mixed and granulated with a solution of sodium lauryl sulfate dissolved in purified water. The mixture was then wet-milled, dried, and sized to obtain a sized powder. The sized powder was mixed with light anhydrous silicic acid, aspartame, and yogurt micron to obtain a fine granule formulation, which was then packaged.

[0064] Examples 8 and 9 Orally disintegrating tablets containing rivaroxaban as the active ingredient were manufactured by compressing a mixture of active ingredient-containing granules, rapidly disintegrating granules, and a lubricant-containing mixture having the composition shown in Table 7. In Table 7, the amount of yogurt micron is so small that the amount of yogurt micron is not included in the "total."

[0065] [Table 7]

[0066] Specifically, rivaroxaban (active ingredient), lactose hydrate (excipient), microcrystalline cellulose (excipient), croscarmellose sodium (disintegrant), and hypromellose (binder) were mixed in a wet high-shear granulator. Separately, hypromellose (binder) and sodium lauryl sulfate (surfactant) were dissolved in purified water in this order. Granulation was performed using this solution. The obtained wet granulated powder was crushed in a dry granulator and dried using a fluidized bed granulation dryer. The obtained dry granulated powder was sized in the dry granulator to prepare granules containing the active ingredient. Furthermore, lactose hydrate (excipient), ethyl cellulose (excipient), light anhydrous silicic acid (disintegrant), and sodium starch glycolate (disintegrant) were mixed in a fluidized bed granulation dryer. Separately, corn starch (disintegrant) was dispersed in purified water to prepare a granulation liquid. The granulation liquid was sprayed onto the mixture, which was then dried and sized using a dry granulator to prepare rapidly disintegrating granules. The active ingredient-containing granules, the rapidly disintegrating granules, ethyl cellulose (excipient), aspartame (sweetener), light anhydrous silicic acid (fluidizer), and yogurt micron (flavoring) were mixed together, and magnesium stearate (lubricant) was further added to obtain tablet powder. The tablet powder was compressed into orally disintegrating tablets using a rotary tablet press.

Claims

1. A compression-molded body containing active ingredient-containing granules containing rivaroxaban as the active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture, the rapidly disintegrating granules comprising an excipient and a disintegrant; An orally disintegrating tablet containing rivaroxaban, wherein the disintegrant contained in the rapidly disintegrating granules comprises either light anhydrous silicic acid or crospovidone.

2. 2. The orally disintegrating tablet containing rivaroxaban according to claim 1, wherein the disintegrant contained in the rapidly disintegrating granules is only disintegrant A consisting of either light anhydrous silicic acid or crospovidone.

3. The disintegrant contained in the rapidly disintegrating granules is a disintegrant A consisting of either light anhydrous silicic acid or crospovidone; The orally disintegrating tablet containing rivaroxaban according to claim 1, which is combined with a disintegrant B consisting of one or more selected from the group consisting of starch, sodium starch glycolate, sodium carboxymethyl starch, carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and calcium carboxymethyl cellulose.

4. The orally disintegrating tablet containing rivaroxaban according to any one of claims 1 to 3, wherein the medicinal ingredient-containing granules contain, in addition to rivaroxaban, an excipient, a disintegrant, and a binder.

5. The orally disintegrating tablet containing rivaroxaban according to any one of claims 1 to 4, wherein the lubricant-containing mixture contains, in addition to the lubricant, an excipient and a glidant.

6. A method for improving the dispersibility of an orally disintegrating tablet containing rivaroxaban, which is a compression molded product containing active ingredient-containing granules containing rivaroxaban as the active ingredient, rapidly disintegrating granules, and a lubricant-containing mixture, comprising: the rapidly disintegrating granules comprising an excipient and a disintegrant; The method for producing the rapidly disintegrating granules, wherein the disintegrant contained in the rapidly disintegrating granules is either light anhydrous silicic acid or crospovidone, or a combination of a disintegrant other than light anhydrous silicic acid and crospovidone and either light anhydrous silicic acid or crospovidone.

7. 1. A method for producing an orally disintegrating tablet containing rivaroxaban, comprising: a step of producing a medicinal ingredient-containing granule containing rivaroxaban as the medicinal ingredient; producing rapidly disintegrating granules comprising an excipient and a disintegrant, wherein the disintegrant comprises either light anhydrous silicic acid or crospovidone; A method comprising the step of mixing the active ingredient-containing granules, the rapidly disintegrating granules, and a lubricant-containing mixture and compressing the mixture.

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