Edoxaban orally disintegrating tablets

Abstract

To provide an orally-disintegrating edoxaban tablet having high storage stability, a method for producing the same, and a method for improving the storage stability of an orally-disintegrating edoxaban tablet.SOLUTION: An orally-disintegrating edoxaban tablet according to the present invention is a compact containing, as medicinal components: medicinal component-containing granules, containing edoxaban; fast-disintegrating granules; and a lubricant. The medicinal component-containing granules contain acidic amino acids.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an edoxaban orally disintegrating tablet having excellent storage stability, a method for producing the same, and a method for improving the storage stability of an edoxaban orally disintegrating tablet.

Background Art

[0002] Edoxaban (chemical name: N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide) cyclohexyl]oxamide) competitively and selectively inhibits human activated blood coagulation factor X (FXa) (Non-Patent Document 1).

[0003] As a form of a commercially available preparation containing edoxaban as an active ingredient, an orally disintegrating tablet that rapidly disintegrates in the mouth by saliva or a small amount of water and releases the active ingredient is sold (Non-Patent Document 1). The researchers of the applicant of the present application have also developed an orally disintegrating tablet that has excellent disintegration characteristics and reduced bitterness, and is a compression molded body containing active ingredient-containing granules, rapidly disintegrating granules, and a lubricant-containing mixture (Patent Documents 1 to 4).

[0004] However, orally disintegrating tablets have a problem that their hardness and shape change during storage because the hydrophilicity and hygroscopicity of their contained components are high. For example, Patent Document 5 discloses an orally disintegrating tablet that exhibits rapid disintegration and solubility, has a good taste in the mouth, and has excellent storage stability, and contains an organic acid such as fumaric acid in addition to edoxaban.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] [Non-Patent Document 1] Lixiana® Tablets 15mg, Lixiana® Tablets 30mg, Lixiana® Tablets 60mg - Package Insert [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] As mentioned above, orally disintegrating tablets containing edoxaban and organic acids as active ingredients are known, but the orally disintegrating tablets actually manufactured in the examples described in Patent Document 5 contain only fumaric acid as an organic acid, and although the thickness and hardness of the tablets are evaluated, their changes over time are not evaluated. Therefore, the present invention aims to provide an edoxaban orally disintegrating tablet with excellent storage stability, a method for producing the same, and a method for improving the storage stability of edoxaban orally disintegrating tablets. [Means for solving the problem]

[0008] The inventors diligently conducted research to solve the aforementioned problems. As a result, they discovered that when obtaining orally disintegrating tablets by mixing granules containing edoxaban, rapidly disintegrating granules, and a lubricant, and then compressing the mixture, the stability of the tablet's shape is improved by adding an acidic amino acid in addition to edoxaban to the granules containing the active ingredient, thus completing the present invention. The present invention is described below.

[0009] [1] A compressed molded body containing granules containing edoxaban as the active ingredient, rapidly disintegrating granules, and a lubricant, Edoxaban orally disintegrating tablets, characterized in that they contain granules containing the aforementioned active ingredient and acidic amino acids. [2] The edoxaban orally disintegrating tablet according to [1], comprising 1% by mass or more and 20% by mass or less of the acidic amino acid relative to the edoxaban in the granules containing the active ingredient. [3] The edoxaban orally disintegrating tablet according to [1] or [2], wherein the acidic amino acid is L-aspartic acid. [4] The edoxaban orally disintegrating tablet according to any one of [1] to [3], wherein the granules containing the active ingredient further contain hydroxypropylcellulose having a viscosity of 2.0 mPa·s or more and 6.0 mPa·s or less in a 2% by mass aqueous solution at 20°C. [5] An edoxaban orally disintegrating tablet according to any one of [1] to [4], wherein the granules containing the active ingredient further contain croscarmellose sodium. [6] The edoxaban orally disintegrating tablet according to any one of [1] to [5] above, wherein the edoxaban is edoxaban tosylate or its hydrate. [7] A method for manufacturing edoxaban orally disintegrating tablets, A process for manufacturing granules containing edoxaban and acidic amino acids as medicinal ingredients. A process for producing rapidly disintegrating granules containing excipients and disintegrants, and A method characterized by comprising the step of mixing the granules containing the active pharmaceutical ingredient, the rapidly disintegrating granules, and a lubricant and then compressing and molding them. [8] The method according to [7], wherein the edoxaban is edoxaban tosylate or its hydrate. [9] A method for improving the storage stability of edoxaban orally disintegrating tablets, which are compressed molded bodies containing edoxaban as a pharmacoactive ingredient, granules containing a pharmacoactive ingredient, rapidly disintegrating granules, and a lubricant, A method characterized by combining the aforementioned granules containing the active pharmaceutical ingredient with an acidic amino acid.

[10] The method according to [9], wherein the edoxaban is edoxaban tosylate or its hydrate. [Effects of the Invention]

[0010] The edoxaban orally disintegrating tablet according to the present invention suppresses changes in shape and hardness such as the thickness of the tablet during storage, and has excellent storage stability. Therefore, the edoxaban orally disintegrating tablet according to the present invention is very excellent industrially as one form of a preparation containing edoxaban as a medicinal ingredient.

Brief Description of the Drawings

[0011] [Figure 1] [[ID=eleven]]Figure 1 is a graph showing the results of the dissolution test of the edoxaban orally disintegrating tablet according to the present invention. [Figure 2] Figure 2 is a graph showing the results of the dissolution test of the edoxaban orally disintegrating tablet according to the present invention. [Figure 3] Figure 3 is a graph showing the results of the dissolution test of the edoxaban orally disintegrating tablet according to the present invention.

Mode for Carrying Out the Invention

[0012] The orally disintegrating tablet according to the present invention contains edoxaban as a medicinal ingredient. The chemical name of edoxaban is N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide) cyclohexyl]oxamide, edoxaban has the following chemical structure, and competitively and selectively inhibits human activated blood coagulation factor X (FXa). [[ID=二十六]]

[0013]

Chemical formula

[0014] Salts of edoxaban may be used as the active ingredient. Examples of such salts include organic acid salts such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, tosylate, and trifluoromethanesulfonate; inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and acidic amino acid salts such as glutamate and aspartate, with tosylate being preferred. Furthermore, edoxaban or its salts may be solvates, with hydrates being preferred and monohydrates being more preferred. That is, in this disclosure, "edoxaban," which is the active ingredient, includes not only compounds with the above chemical structures but also its salts and their solvates.

[0015] The size of the raw material, edoxaban, can be adjusted as needed. For example, the cumulative 50% particle size (D) based on volume. 50 The particle size can be 1 μm or more and 70 μm or less, and preferably 3 μm or more and 40 μm or less. Therefore, if the crystal grains of the raw material edoxaban are large, it is preferable to grind them beforehand. Note that in this disclosure, the cumulative 50% particle size (D) is based on volume. 50 ) shall be measured on a volume basis using a laser diffraction particle size distribution analyzer.

[0016] The amount and proportion of edoxaban in the orally disintegrating tablets according to the present invention may be adjusted as appropriate within a range in which edoxaban can exert its effects. For example, the amount of edoxaban per tablet can be 1 mg or more and 100 mg or less, preferably 5 mg or more, more preferably 10 mg or more, preferably 80 mg or less, more preferably 60 mg or less, and even more preferably 15 ± 0.15 mg, 30 ± 0.3 mg, 40 ± 0.4 mg, or 60 ± 0.6 mg. The proportion of edoxaban in the orally disintegrating tablets 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 even more preferably 40% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less. Note that when using a salt of edoxaban or its solvate as a raw material, the above amounts and proportions refer to the amount and proportion of edoxaban itself, excluding counter anions and solvents.

[0017] The edoxaban-containing orally disintegrating tablet according to the present invention is a compressed molded body containing granules containing edoxaban as the active ingredient, rapidly disintegrating granules, and a lubricant.

[0018] The granules containing the active ingredient edoxaban contain not only the active ingredient edoxaban, but also common ingredients such as excipients, disintegrants, and binders, as well as acidic amino acids.

[0019] Excipients are additives added to improve the moldability and ease of administration of a formulation by diluting the active ingredient or increasing the volume of the formulation. Examples of excipients include mannitol, crystalline cellulose, lactose, ethylcellulose, starch, dextrin, and sucrose. One type of excipient may be used alone, or two or more may be used in combination. The amount of excipient in the granules containing the active ingredient may be adjusted as appropriate, but for example, it can be 10% by mass or more and 70% by mass or less of the total granules containing the active ingredient, preferably 20% by mass or more, preferably 60% by mass or less, and more preferably 50% by mass or less.

[0020] Disintegrants are components added to tablets to absorb moisture and promote disintegration, thereby facilitating the release of the active ingredient. While there are no particular limitations on disintegrants, examples include croscarmellose sodium, carmellose, starch, sodium starch glycolate, carmellose sodium, carboxymethylcellulose calcium, light anhydrous silicic acid, and crospovidone. One type of disintegrant may be used, or two or more may be used in combination. The amount and proportion of disintegrants in granules containing the active ingredient should be adjusted appropriately within a range that allows the tablet to disintegrate well after administration and release the active ingredient. For example, the amount of disintegrant can be 1% or more by mass and 20% or less by mass relative to the total amount of granules containing the active ingredient, preferably 2% or more by mass, more preferably 4% or more by mass, and preferably 15% or less by mass.

[0021] It is preferable to include croscarmellose sodium and / or carmellose as at least a portion of the disintegrant in the granules containing the active ingredient. According to experimental findings by the present inventors, by including at least one selected from croscarmellose sodium and carmellose as at least a portion of the excipient in the granules containing the active ingredient, the dissolution of edoxaban in low pH environments such as the stomach is improved. The amount of croscarmellose sodium and / or carmellose can be adjusted as appropriate, but for example, it can be 0.01 parts by mass or more and 0.5 parts by mass or less per 1 part by mass of edoxaban, which is the active ingredient.

[0022] A binder is an ingredient added to bind the components together and increase the strength of the granules or tablets. While there are no particular limitations on the binder, examples include hydroxypropylcellulose, hypromellose, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylcellulose-polyvinylpyrrolidone, polyvinyl alcohol, and ethylcellulose. Only one binder may be used, or two or more may be used in combination. The amount and proportion of the binder in the granules containing the active ingredient should be adjusted as appropriate according to the desired granule strength or tablet strength. For example, the amount can be 0.1% by mass or more and 20% by mass or less relative to the total amount of the granules containing the active ingredient. Preferably, the proportion is 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 2% by mass or more, and preferably 15% by mass or less, with 10% by mass or less being the most preferable.

[0023] It is preferable to incorporate hydroxypropyl cellulose as at least a portion of the binder in the granules containing the active ingredient. According to experimental findings by the present inventors, incorporating hydroxypropyl cellulose as at least a portion of the excipient in the granules containing the active ingredient improves the dissolution of edoxaban in low pH environments such as the stomach. Preferably, the hydroxypropyl cellulose has a viscosity of 2.0 mPa·s or more and 6.0 mPa·s or less at 20°C in a 2% by mass aqueous solution, and more preferably 2.0 mPa·s or more and 3.0 mPa·s or less. The amount of hydroxypropyl cellulose can be adjusted as appropriate, but for example, it can be 0.01 parts by mass or more and 0.5 parts by mass or less per 1 part by mass of edoxaban, which is the active ingredient.

[0024] The present invention provides edoxaban orally disintegrating tablets with excellent storage stability by incorporating acidic amino acids into granules containing the active ingredient, thereby suppressing changes in tablet thickness and hardness during storage. Examples of acidic amino acids include aspartic acid and glutamic acid. One type of acidic amino acid may be used alone, or two or more types may be used in combination, but aspartic acid is preferably used. Furthermore, L-acidic amino acids are preferred as the acidic amino acid.

[0025] The amount of acidic amino acids can be adjusted as appropriate, but for example, it can be 0.1% by mass or more and 10% by mass or less relative to the total amount of granules containing the active ingredient. Preferably, it is 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 1.5% by mass or more, and also preferably 8% by mass or less, more preferably 5% by mass or less, and even more preferably 3% by mass or less. In addition, the amount of acidic amino acids can be 1% by mass or more and 20% by mass or less relative to edoxaban. Preferably, it is 1.5% by mass or more, more preferably 2% by mass or more, even more preferably 4% by mass or more, and also preferably 20% by mass or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less.

[0026] The size of the granules containing the active ingredient can be adjusted as appropriate. For example, the average particle size (D 50 The particle size can be 30 μm or more and 300 μm or less, and preferably 50 μm or more and 200 μm or less.

[0027] Rapidly disintegrating granules are granules that absorb moisture in the oral cavity to rapidly promote the disintegration of the orally disintegrating tablets according to the present invention, thereby accelerating the release of the active ingredient, edoxaban. Rapidly disintegrating granules contain at least an excipient and a disintegrant. They may also contain a coloring agent.

[0028] Excipients used in rapidly disintegrating granules are the same as those used in granules containing active pharmaceutical ingredients, but they may be the same or different from each other. The amount of excipient in rapidly disintegrating granules can be adjusted as appropriate, but for example, it can be 50% or more and 95% or less by mass relative to the total amount of rapidly disintegrating granules, preferably 60% or more by mass, more preferably 70% or more by mass, more preferably 90% or less by mass, and even more preferably 80% or less by mass.

[0029] The disintegrants used in rapidly disintegrating granules are similar to those used in excipients for granules containing active pharmaceutical ingredients, but they may be the same or different. The amount of disintegrant in rapidly disintegrating granules can be adjusted as appropriate, but for example, it can be 10% by mass or more and 50% by mass or less of the total amount of rapidly disintegrating granules, preferably 15% by mass or more, more preferably 20% by mass or more, and preferably 40% by mass or less, and more preferably 30% by mass or less.

[0030] Rapidly disintegrating granules may contain a binder. Examples of binders used in rapidly disintegrating granules include those used in granules containing active pharmaceutical ingredients, but they may be the same or different. The amount of binder in rapidly disintegrating granules can be adjusted as appropriate, but for example, it can be 0.1% by mass or more and 15% by mass or less relative to the total amount of rapidly disintegrating granules. Preferably, the amount is 1% by mass or more, more preferably 2% by mass or more, even more preferably 5% by mass or more, and preferably 10% by mass or less, with a further preference of 8% by mass or less.

[0031] Furthermore, the rapidly disintegrating granules may contain a coloring agent. The coloring agent used in the rapidly disintegrating granules is not particularly limited, but examples include metal oxides such as ferric oxide, yellow ferric oxide, titanium dioxide, and zinc oxide; talc; and barium sulfate. Only one coloring agent may be used, or two or more may be used in combination. The amount and proportion of the coloring agent can be adjusted as appropriate, for example, within a range sufficient to color the entire rapidly disintegrating granule or tablet. It may be a very small amount, but for example, it can be 0.01% by mass or more and 0.5% by mass or less relative to the total amount of rapidly disintegrating granules.

[0032] The size of rapidly disintegrating granules can be adjusted as needed. For example, the average particle diameter (D 50 The thickness can be 30 μm or more and 200 μm or less, and preferably 40 μm or more and 150 μm or less.

[0033] The edoxaban orally disintegrating tablets according to the present invention contain at least a lubricant in addition to granules containing the active ingredient and rapidly disintegrating granules. The lubricant promotes good mixing of the granules containing the active ingredient and the rapidly disintegrating granules, and facilitates the tableting of these mixtures. Furthermore, the granules containing the active ingredient and the rapidly disintegrating granules may be mixed with other additives such as excipients, disintegrants, fluidizers, sweeteners, and flavorings in addition to the lubricant before tableting.

[0034] Lubricants are added to the surface of each component to increase its fluidity or to prevent the component from adhering to the device. While there are no particular limitations on lubricants, examples include magnesium stearate, talc, hydrogenated vegetable oil, polyglycerin fatty acid esters, and sucrose fatty acid esters. One lubricant may be used alone, or two or more may be used in combination, but magnesium stearate is preferred. The amount and proportion of the lubricant should be adjusted appropriately within a range that allows for good tableting. For example, it can be 0.01% by mass or more and 10% by mass or less of the total tablet weight. The preferred proportion is 0.2% by mass or more, more preferably 0.5% by mass or more, and more preferably 5% by mass or less, with 2% by mass or less being even more preferred.

[0035] Excipients and disintegrants mixed with granules containing active ingredients and rapidly disintegrating granules are the same as those used in the granules containing active ingredients and rapidly disintegrating granules, but they may be the same or they may be different from each other.

[0036] A fluidizing agent is an ingredient added to enhance the fluidity of each component contained in granules containing medicinal ingredients, rapidly disintegrating granules, and lubricants, so that they can be mixed uniformly and quickly. While there are no particular limitations on the fluidizing agent, examples include light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, and talc. One fluidizing agent may be used alone, or two or more may be used in combination.

[0037] Sweeteners are added to tablets to mitigate bitterness and other unpleasant tastes. While there are no particular restrictions on the type of sweetener, examples include aspartame, saccharin, erythritol, and sucrose. Only one type of sweetener may be used, or two or more may be used in combination. The amount and proportion of sweeteners can be adjusted as appropriate, but for example, it can be between 0.1% and 10% by mass relative to the total tablet weight, preferably 0.2% or more, more preferably 0.5% or more, and preferably 5% or less, with 2% or less being even more preferable.

[0038] The flavoring is an ingredient that imparts aroma to the tablet. There are no particular restrictions on the flavoring, but for example, peppermint micron, yogurt flavoring, peach flavoring, grapefruit flavoring, apple flavoring, acerola flavoring, plum flavoring, plum juice flavoring, coffee flavoring, black tea flavoring, etc., can be used. Only one flavoring may be used, or two or more may be used in combination. The amount and proportion of the flavoring can be adjusted as appropriate, but while even a small amount of flavoring can emit an aroma, too much may make it difficult to administer. Therefore, it is preferable to use a small amount, for example, 0.5% by mass or less of the total tablet weight.

[0039] The edoxaban-containing orally disintegrating tablet according to the present invention can be manufactured by general methods, as long as it has the above-mentioned component composition. For example, the edoxaban-containing orally disintegrating tablet according to the present invention can be manufactured by a method comprising the steps of: manufacturing granules containing edoxaban as the pharmacoactive ingredient; manufacturing rapidly disintegrating granules containing excipients and disintegrants; and mixing the pharmacoactive ingredient-containing granules, the rapidly disintegrating granules, and at least a lubricant and then compressing them.

[0040] Pharmacologically active ingredient-containing granules and rapidly disintegrating granules can be manufactured according to general granule manufacturing methods, as long as the pharmacokinetic ingredient-containing granules contain edoxaban as the pharmacokinetic ingredient. For example, granules can be manufactured by a wet granulation method in which a solvent is sprayed onto finely ground raw material powder that has been rolled or flowed to bind it together, or by a dry granulation method in which a lubricant is added to the raw material powder, pressure is applied to form it into a bulk shape such as a plate, and then it is crushed and sized. Manufacture by the wet granulation method is preferred.

[0041] Next, the granules containing the active ingredient and the rapidly disintegrating granules are mixed with a lubricant and, if necessary, other additives, and then compressed into tablets using a tableting machine.

[0042] The moisture content of the edoxaban-containing orally disintegrating tablets according to the present invention is not particularly limited, but it is preferable to adjust the manufacturing conditions of each granule, for example, so that the moisture content is 5% by mass or less. Preferably, the moisture content is 3% by mass or less. The lower limit of the moisture content is not particularly limited and may be 0% by mass, but the moisture content can be, for example, 0.1% by mass or more. The moisture content can be measured, for example, by the Karl Fischer method.

[0043] The hardness of the edoxaban-containing orally disintegrating tablets according to the present invention is not particularly limited, but for example, a hardness of 20 N or more and 100 N or less is preferred. This hardness can be adjusted, for example, by the compression pressure. The decrease in hardness of the edoxaban-containing orally disintegrating tablets according to the present invention during storage is suppressed by incorporating an acidic amino acid into the granules containing the active ingredient.

[0044] The size of the tablets of the present invention may be adjusted as appropriate. For example, the shape of the tablets may be a disc or lens shape that is easy to swallow orally, with a diameter of 4 mm or more and 10 mm or less, and a thickness of 2 mm or more and 5 mm or less. Alternatively, the shape of the tablets of the present invention may be elliptical or elliptical-like, in which case the major axis may be 10 mm or more and 15 mm or less, and the thickness may be 5 mm or more and 10 mm or less.

[0045] The dosage of the edoxaban-containing orally disintegrating tablets according to the present invention may be adjusted as appropriate depending on the patient's symptoms, severity, age, sex, etc. For example, it is sufficient to administer 20 mg to 80 mg per day, converted to the equivalent dose of edoxaban, in one or two divided doses. The dosage may also be reduced or increased depending on concomitant medications. When edoxaban salts or solvates are administered, the amount should be converted to the equivalent dose of edoxaban alone.

[0046] As mentioned above, the inventors have found that by incorporating an acidic amino acid into the granules containing the active ingredient that make up orally disintegrating tablets, changes in the thickness and hardness of the tablets during storage are suppressed, and the storage stability of the orally disintegrating tablets is improved. Therefore, in the present invention, by incorporating an acidic amino acid into the granules containing the active ingredient, the storage stability of edoxaban orally disintegrating tablets, which are a compressed molded body containing granules containing the active ingredient edoxaban, rapidly disintegrating granules, and a lubricant, is improved. [Examples]

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited by the following examples, and it is certainly possible to implement it with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of the present invention.

[0048] Example 1: Manufacturing and storage stability testing of edoxaban orally disintegrating tablets (1) Manufacturing of edoxaban orally disintegrating tablets Edoxaban orally disintegrating tablets having the composition shown in Table 1 were manufactured. Specifically, edoxaban tosylate hydrate, D-mannitol, hydroxypropyl cellulose ("HPC-SSL," manufactured by Nippon Soda Co., Ltd., viscosity of 2% by mass aqueous solution at 20°C: 2.0-2.9 mPa·s), crystalline cellulose, crospovidone, carmellose, and L-aspartic acid were placed in a stirring granulator and mixed, then granulated by spraying with purified water. Next, the resulting particles were crushed, dried using a fluidized bed granulator, and then sized to prepare granules containing the active ingredient. Furthermore, D-mannitol, ethylcellulose, and light anhydrous silicic acid were introduced into a fluidized bed granulator, and a dispersion of corn starch and crospovidone in purified water was sprayed onto the mixture. The resulting particles were dried and sized to prepare rapidly disintegrating granules. Edoxaban orally disintegrating tablets were obtained by mixing the granules containing the aforementioned active ingredient, rapidly disintegrating granules, and aspartame, and then further mixing in magnesium stearate before compressing the mixture into tablets. For comparison, edoxaban orally disintegrating tablets of Comparative Examples 1 and 2 were manufactured in the same manner, except that fumaric acid or succinic acid was used instead of L-aspartic acid.

[0049] [Table 1]

[0050] (2) Storage stability test Each of the obtained tablets was placed unpackaged in a constant temperature and humidity chamber ("SRH-30VEVJ2," manufactured by Nagano Science Co., Ltd.) and maintained at 40°C and 75%RH for one month. Before and after storage, the hardness of the tablets was measured using a tablet hardness tester ("TBH425TD," manufactured by ERWEKA), and the thickness of the tablets was measured using a dial thickness gauge (manufactured by Ozaki Seisakusho). The results are shown in Table 2.

[0051] [Table 2]

[0052] As shown in the results of Comparative Examples 1 and 2 in Table 2, edoxaban orally disintegrating tablets contain many hydrophilic components and are particularly susceptible to deterioration under high humidity conditions. After being stored for one month under conditions of 75% relative humidity and 40°C, their hardness decreased and their thickness increased. In contrast, the tablets of Example 1, which contained L-aspartic acid as an organic acid in granules containing the active ingredient, showed minimal changes in hardness and tablet thickness even after being stored for one month under the same conditions, demonstrating excellent storage stability.

[0053] Examples 2 and 3: Investigation of disintegrants (1) Manufacturing of edoxaban orally disintegrating tablets Edoxaban orally disintegrating tablets having the composition shown in Table 3 were manufactured. Specifically, edoxaban tosylate hydrate, D-mannitol, hydroxypropyl cellulose ("HPC-SSL," manufactured by Nippon Soda Co., Ltd., viscosity of a 2% by mass aqueous solution at 20°C: 2.0-2.9 Pa·s), L-aspartic acid, and crospovidone or croscarmellose sodium as a disintegrant were added to a stirring granulator and mixed, then granulated by spraying with purified water. Next, the resulting particles were crushed, dried using a fluidized bed granulator, and then sized to prepare granules containing the active ingredient. Furthermore, D-mannitol, ethylcellulose, and light anhydrous silicic acid were introduced into a fluidized bed granulator, and a dispersion of corn starch, ferric oxide, and crospovidone as a disintegrant in purified water was sprayed onto the mixture. The resulting particles were dried and sized to prepare rapidly disintegrating granules. Edoxaban orally disintegrating tablets were obtained by mixing the granules containing the aforementioned active ingredient, rapidly disintegrating granules, crospovidone, aspartame, and fragrance, and then further mixing in magnesium stearate before compressing the mixture into tablets. Note that the amounts of ferric oxide and fragrance in Table 3 are very small and therefore not included in the subdivision and total amounts.

[0054] [Table 3]

[0055] (2) Dissolution test Next, a dissolution test was performed in accordance with the 18th edition of the Japanese Pharmacopoeia. Specifically, a flow-through cell dissolution tester was used, which included a test solution storage tank, a liquid delivery pump, a flow-through cell, and a constant temperature water bath, in accordance with the apparatus for the flow-through cell method described in 6.10 Dissolution Test Method 1.3. Flow-through Cell Method of the 18th edition of the Japanese Pharmacopoeia. I placed beads with a diameter of approximately 5 mm in the conical lower part of the flow-through cell, and then placed glass beads with a diameter of approximately 1 mm on top of them. Tablets were placed one by one in a tablet holder, and a pH 1.2 test solution adjusted to 37±0.5℃ was introduced into a flow-through cell at a rate of 4 mL / min. After 60 minutes, the amount of edoxaban in the test solution sample was measured using a UV-Vis spectrophotometer. The results are shown in Figure 1. As shown in Figure 1, the total amount of edoxaban released was almost the same whether the disintegrant in the edoxaban orally disintegrating tablets contained crospovidone or croscarmellose sodium. However, it was found that edoxaban was released more quickly in low pH environments such as the stomach when croscarmellose sodium was used. Therefore, it has become clear that when it is desirable to release edoxaban more quickly from orally disintegrating tablets in the stomach, it is preferable to use croscarmellose sodium as a disintegrant in the granules containing the active ingredient.

[0056] Examples 4 and 5: Investigation of the amount of disintegrant used Edoxaban orally disintegrating tablets were manufactured in the same manner as in Examples 2 and 3(1), except that the composition was changed to that shown in Table 4. Note that the amounts of ferric oxide and fragrance in Table 4 are very small and therefore are not included in the sub-measurements and total amounts.

[0057] [Table 4]

[0058] Furthermore, the dissolution rate was determined in the same manner as in Examples 2 and 3(2), except that the amount of edoxaban in the test solution sample was measured at a predetermined time. The results are shown in Figure 2. As shown in Figure 2, doubling the amount of crospovidone, the disintegrant contained in the granules of the active ingredient of edoxaban orally disintegrating tablets, did not significantly change the dissolution properties of edoxaban under low pH conditions. This indicates that, at least within the scope of this experiment, the amount of crospovidone does not affect the dissolution properties of edoxaban.

[0059] Examples 6 and 7: Investigation of binders Hydroxypropylcellulose ("HPC-SSL," manufactured by Nippon Soda Co., Ltd.) or vinylpyrrolidone-vinyl acetate copolymer ("Kollidone") are used as binders in granules containing medicinal ingredients. (R) Edoxaban orally disintegrating tablets were manufactured in the same manner as in Examples 2 and 3(1), except that the composition was changed to that shown in Table 5, using "VA64" (manufactured by BASF). Note that the amounts of ferric oxide and flavoring in Table 5 are very small and therefore not included in the sub-measurements and total amounts.

[0060] [Table 5]

[0061] Furthermore, the amount of edoxaban in the test solution sample was measured at a predetermined time, in the same manner as in Examples 2 and 3(2). The results are shown in Figure 3. As shown in Figure 3, it was found that edoxaban orally disintegrating tablets containing hydroxypropylcellulose as a binder released edoxaban more quickly in low-pH environments such as the stomach compared to edoxaban orally disintegrating tablets containing vinylpyrrolidone-vinyl acetate copolymer as a binder. Therefore, it has become clear that when it is desirable to release edoxaban more quickly from orally disintegrating tablets in the stomach, it is preferable to use hydroxypropylcellulose as a binder incorporated into the granules containing the active ingredient.

[0062] Examples 8, 9 Edoxaban orally disintegrating tablets having the composition shown in Table 6 were manufactured. Specifically, edoxaban tosylate hydrate, D-mannitol, hydroxypropyl cellulose ("HPC-SSL," manufactured by Nippon Soda Co., Ltd., viscosity of 2% by mass aqueous solution at 20°C: 2.0-2.9 Pa·s), carmellose or croscarmellose sodium, and L-aspartic acid were placed in a stirring granulator and mixed, then granulated by spraying with purified water. Next, the resulting particles were crushed using a screen diameter of 6350 μm, dried using a fluidized bed granulator, and then sized using a screen diameter of 1575 μm to prepare granules containing the active ingredient. Furthermore, D-mannitol, ethylcellulose, and light anhydrous silicic acid were fed into a fluidized bed granulator, and a dispersion of corn starch, crospovidone, and ferric oxide dispersed in purified water was sprayed onto the mixture. The resulting particles were dried and sieved through a 30M sieve to prepare rapidly disintegrating granules. A portion of the rapidly disintegrating granules, aspartame, and fragrance were mixed and sieved through a 30M sieve to obtain a double-spread sieved powder. The granules containing the active ingredient and the remainder of the rapidly disintegrating granules were mixed in a diffusion mixer, the double-spread sieved powder was mixed with magnesium stearate, and the mixture was compressed in a rotary tablet press to obtain edoxaban orally disintegrating tablets. Note that in Table 6, the amounts of ferric oxide and fragrance are very small and therefore not included in the small-scale weighing and total amounts.

[0063] [Table 6]

Claims

1. A method for improving the storage stability of edoxaban orally disintegrating tablets, which are compressed molded bodies containing granules containing edoxaban as a pharmacoactive ingredient, rapidly disintegrating granules, and a lubricant, characterized in that L-aspartic acid is incorporated into the granules containing the pharmacoactive ingredient.

2. The method according to claim 1, wherein the edoxaban is edoxaban tosylate or its hydrate.

3. The method according to claim 1 or 2, wherein the granules containing the active ingredient contain 1% by mass or more and 20% by mass or less of L-aspartic acid relative to edoxaban.

4. The method according to any one of claims 1 to 3, wherein the granules containing the active ingredient further comprises hydroxypropyl cellulose having a viscosity of 2.0 mPa·s or more and 6.0 mPa·s or less in a 2% by mass aqueous solution at 20°C.

5. The method according to any one of claims 1 to 4, wherein the granules containing the pharmacoactive ingredient further contain croscarmellose sodium.

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