JP2022113667A - Edoxaban-containing pharmaceutical composition - Google Patents

Abstract

To provide an edoxaban-containing pharmaceutical composition that ensures excellent solubility of edoxaban in the neutral region.SOLUTION: A pharmaceutical composition contains granules containing (A) edoxaban, a pharmacologically acceptable salt (for example, tosilate), or a solvate thereof (for example, a hydrate), and (B) a water-soluble binder and is free of organic acids. The granules are ones wet-granulated by using a dispersion of (A) and (B).SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical composition containing edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof (hereinafter sometimes referred to as "edoxaban etc."). The present invention relates inter alia to solid pharmaceutical compositions containing edoxaban tosilate hydrate.

Edoxaban has the chemical name N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide. Edoxaban, its pharmacologically acceptable salts, or solvates thereof exhibit an inhibitory effect on activated blood coagulation factor X, and are particularly useful for the prevention and/or treatment of thrombosis or embolism. It is known.

In pharmaceutical compositions for oral administration such as tablets and capsules, the dissolution of medicinal ingredients has a great effect on efficacy and safety, and therefore standards for dissolution are established in each country. For example, in Japan, a dissolution test method is described in the Japanese Pharmacopoeia, and various dissolution test solutions (hereinafter also referred to as test solutions or dissolution solutions) are defined for the dissolution test. These dissolution test solutions include strongly acidic dissolution test solutions (e.g., the first solution described in the Japanese Pharmacopoeia, 0.1 N hydrochloric acid aqueous solution, etc.), pH 3-5 dissolution test solutions (e.g., acetic acid-sodium acetate buffer solution, etc.), pH 6.8 dissolution test solution (for example, the second solution described in the Japanese Pharmacopoeia, pH 6.8 phosphate buffer, etc.), water, and the like are shown. Formulations for oral administration are required to have good dissolution properties in dissolution tests using these dissolution test solutions.

Edoxaban is a basic compound, and although it exhibits good solubility in strongly acidic aqueous solutions, its solubility decreases in neutral aqueous solutions (e.g., neutral buffer solutions). It is necessary to improve the solubility in aqueous solutions of The following documents describe formulations intended to improve the dissolution and absorbability of edoxaban and the like.

International Publication No. WO2008/129846 (Patent Document 1) describes a pharmaceutical composition containing (a) edoxaban and (b) one or more selected from sugar alcohols and water-swellable additives, and A coated tablet coated with (c) a coating agent in addition to (a) and (b) is described.

International Publication No. WO2010/147169 (Patent Document 2) further describes a pharmaceutical composition in which the dissolution of edoxaban is improved by reducing the proportion of edoxaban in the pharmaceutical composition to 0.5 to 15 parts by weight. ing.

International Publication No. WO2011/115067 (Patent Document 3) describes (a) edoxaban, (b) excipients that are sugar alcohols and/or water-swellable additives, (c) disintegrants and (d) binders. A pharmaceutical composition is described in which the solubility in the neutral region of the formulation is improved by keeping the maximum water content of the granules at 10% or less during granulation.

In International Publication No. WO2013/022059 (Patent Document 4), edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, and carboxylic Solid formulations such as tablets or capsules containing acids or enols or their salts have been proposed.

International Publication No. WO2016/020080 discloses a pharmaceutical composition comprising edoxaban, or a pharmaceutically acceptable salt thereof, a water-soluble vinylpyrrolidone polymer selected from the group consisting of povidone and copovidone, and a cellulose ether things are described.

In International Publication No. WO2018/101373 (Patent Document 6), edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof, an organic acid, 0.1 to 2.0 weight relative to the total weight of the tablet % water-soluble polymer, and an orally disintegrating tablet containing a disintegrant.

International Publication No. WO2008/129846 International Publication No. WO2010/147169 International Publication No. WO2011/115067 International Publication No. WO2013/022059 International Publication No. WO2016/020080 International Publication No. WO2018/101373

However, the compositions described in Patent Documents 1 to 6 do not have sufficient dissolution properties in the neutral region.

An object of the present invention is to provide a pharmaceutical composition containing edoxaban and the like with improved dissolution properties in the neutral region.

As a result of intensive studies, the present inventors have found that dispersion of (A) edoxaban and the like and (B) a water-soluble binder without using an organic acid, that is, a compound that is an organic substance that can be used as a pharmaceutical additive and exhibits acidity. It was found that wet granulation of a liquid improves the dispersibility of edoxaban and the like in a neutral aqueous solution, and improves the dissolution of edoxaban and the like in the neutral region. This is presumably because the water-soluble binder and the edoxaban or the like are in a more contact state, and the wettability of the edoxaban or the like is improved. Based on this finding, the present invention is configured as follows.

A pharmaceutical composition according to the present invention comprises (A) edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (B) a granule containing a water-soluble binder, wherein the organic acid does not include The granules are granules obtained by wet granulation using the dispersions of (A) and (B).

By doing so, it is possible to provide a pharmaceutical composition containing edoxaban etc. in which the dispersibility of edoxaban etc. in a neutral aqueous solution is improved and the dissolution of edoxaban etc. in the neutral region is improved.

INDUSTRIAL APPLICABILITY According to the present invention, a pharmaceutical composition having improved dispersibility in a neutral aqueous solution of edoxaban and the like and improved dissolution of edoxaban and the like can be obtained.

In addition, the pharmaceutical composition of the present invention has suppressed bitterness, and can contribute to improvement of patient compliance.

1 is a diagram showing the dissolution properties of edoxaban in Example 1 of the present invention and Comparative Example. FIG.

A pharmaceutical composition according to the present invention comprises (A) edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (B) a granule containing a water-soluble binder, wherein the organic acid does not include The granules are granules obtained by wet granulation using the dispersions of (A) and (B).

In the present invention, edoxaban may be a solvate, or a solvate (eg, hydrate) of a pharmacologically acceptable salt (eg, tosylate) of edoxaban.

Edoxaban pharmacologically acceptable salts include hydrochloride, sulfate, hydrobromide, citric acid, hydroiodide, phosphate, nitrate, benzoate, methanesulfonate, benzenesulfonate. , 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, fumarate, malate, mandelate, and the like. The hydrochloride, tartrate or tosylate (ie p-toluenesulfonate) is preferred, with the tosylate being especially preferred.

A solvent for dispersing edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof is not particularly limited as long as it is a pharmacologically acceptable solvent. Water is preferred as such a solvent, and purified water can be used in particular.

The water-soluble binder is preferably a commonly used pharmacologically acceptable water-soluble binder, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol (partially saponified product), pullulan, starch, dextrin. , gelatin and the like. Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol (partially saponified product) are more preferred. Water-soluble cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose are more preferred. In the present invention, one or more compounds selected from the above water-soluble binders can be dissolved in a solvent and used in a dispersion of edoxaban or the like. Preferably, one compound selected from the above is used. Hydroxypropyl cellulose is particularly preferred. The water-soluble binder is preferably in the range of 0.1 to 10 parts by weight, and in the range of 0.5 to 3 parts by weight, relative to 100 parts by weight of the edoxaban-containing pharmaceutical composition. is more preferable.

Granules contained in the pharmaceutical composition of the present invention are preferably wet granules obtained by spraying dispersions of (A) and (B) onto powder additives. By granulating in this manner, the elution of edoxaban and the like in the neutral region is improved even without containing an organic acid.

At least one pharmaceutically acceptable additive selected from excipients, disintegrants, and stabilizers can be used as the powder additive. Preferably, conventional excipients that are pharmacologically acceptable can be used. Examples of such excipients include starches such as crystalline cellulose and corn starch, sugars such as sucrose, lactose and glucose, sugar alcohols such as mannitol, erythritol, xylitol and sorbitol, light anhydrous silicic acid, talc, Magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydrogen phosphate, tribasic calcium phosphate and the like. These excipients may be used alone or in combination of two or more, but sugar alcohols (eg, mannitol, erythritol, xylitol, sorbitol, etc.) are preferred, and mannitol is particularly preferred.

The powder additive is preferably in the range of 0.1 to 30 parts by weight, more preferably in the range of 10 to 20 parts by weight with respect to 100 parts by weight of the edoxaban-containing pharmaceutical composition. more preferred.

Moreover, in the present invention, a water-insoluble polymer and/or an inorganic substance may be used as a powder additive. When the granules contain an excipient and a water-insoluble polymer and/or an inorganic substance, the dispersibility of the granules is improved, the disintegration property is improved, and gelation of edoxaban etc. is prevented, and the pharmaceutical composition can be used as a tablet. It can improve the disintegration of tablets and the dissolution of edoxaban, etc., when used.

As a powder additive, a water-insoluble polymer or an inorganic substance can be used alone, or at least one of the excipients, disintegrants, and stabilizers described above can be used as a pharmacologically acceptable additive. A mixture of a water-insoluble polymer and an inorganic substance can be used. In this case, the excipient and the inorganic substance may be the same compound. Unlike excipients and inorganic substances, it is more preferable to use crystalline cellulose, starches, sugars, and sugar alcohols as excipients when inorganic substances are used.

Further, it is preferable to wet granulate by spraying a dispersion of edoxaban or the like and a water-soluble binder to a mixture of the excipient and the water-insoluble polymer and/or inorganic substance. This can further improve the dispersibility of edoxaban and the like.

Examples of water-insoluble polymers include ethyl cellulose, cellulose acetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, vinyl acetate resins, and mixtures of one or more of them. Examples of inorganic substances include magnesium carbonate and carbonate. Calcium, magnesium aluminometasilicate, magnesium aluminosilicate, calcium silicate, magnesium silicate, talc, magnesium oxide, magnesium hydroxide, calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate and one or two thereof Mixtures of more than one species are included. Ethyl cellulose is particularly preferably used as the water-soluble polymer and/or inorganic substance.

The water-insoluble polymer or inorganic substance is preferably in the range of 0.1 parts by weight or more and 20 parts by weight or less, more preferably 5 parts by weight or more and 10 parts by weight or less, relative to 100 parts by weight of the pharmaceutical composition containing the present invention. preferable.

The pharmaceutical composition according to the present invention comprises the granules thus obtained and one or more pharmacologically acceptable additives selected from excipients, disintegrants, binders and lubricants. It can be a pharmaceutical composition in combination with. The pharmaceutical composition of the present invention may further contain other conventional pharmacologically acceptable additives such as preservatives, flavoring agents, sweetening agents, coloring agents, flavoring agents, flavoring agents, and the like. good.

Examples of excipients include starches such as crystalline cellulose and corn starch, sugars such as sucrose, lactose and glucose, sugar alcohols such as mannitol, erythritol, xylitol and sorbitol, light anhydrous silicic acid, talc, magnesium oxide, Magnesium carbonate, calcium carbonate, anhydrous calcium hydrogen phosphate, tribasic calcium phosphate and the like. These excipients may be used alone or in combination of two or more.

Examples of disintegrants include crystalline cellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, crospovidone, starches, and the like. be done. These disintegrants may be used alone or in combination of two or more.

Binders include pharmacologically acceptable binders such as sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose (carmellose), crystalline cellulose/sodium carboxymethylcellulose, polyvinyl pyrrolidone, pullulan, dextrin, tragacanth, sodium alginate, pregelatinized starch, polyvinyl alcohol and the like. These binders may be used alone or in combination of two or more.

Examples of lubricants include magnesium stearate, light anhydrous silicic acid, talc, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, and L-leucine. Examples of sweeteners include sugars such as sucrose, lactose and glucose, sugar alcohols such as mannitol, erythritol, xylitol and sorbitol, aspartame, sucralose, acesulfame potassium and thaumatin. These other commonly used additives may be used alone or in combination of two or more.

Next, a method for producing a pharmaceutical composition according to the present invention will be described.

First, after adding a water-soluble binder to a solvent and dissolving it with a stirrer, edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof is added to this solvent and dispersed by a dispersing device. Prepare liquid.

Next, the dispersion of edoxaban or the like and a water-soluble binder is wet granulated with or without powder additives to obtain granules. The granulation operation can be carried out using, for example, a fluidized bed granulator, agitation granulator, twin-screw granulator, or the like. Moreover, when granulating without using a powder additive, it can be carried out according to the steps described in International Publication WO2014/181390. In this embodiment, it is preferable to use a fluidized bed granulation method that can continuously perform wet granulation and drying using a dispersion of edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof. .

The resulting granules are dried and granulated by a conventional method to obtain a pharmaceutical composition.

As described above, the powder additive contains one or more pharmacologically acceptable additives selected from excipients, disintegrants, binders, and lubricants, and if necessary, water-insoluble polymers and inorganic substances. can be used. Therefore, for example, if (B) a water-soluble cellulose derivative is used as a water-soluble binder, a water-insoluble polymer ethyl cellulose is used as a powder additive, and if desired, an excipient (sugar alcohol, etc.) is used for granulation. , edoxaban, a cellulose derivative (ie, ethyl cellulose and a water-soluble cellulose derivative), and optionally an excipient (sugar alcohol, etc.).

After sizing, an excipient, a disintegrant, a binder, a lubricant and the like can be mixed as a rear end portion and tableted. Alternatively, after sizing, particles separately granulated using excipients, disintegrants, binders, etc., may be added together with a lubricant as the trailing portion and then tableted. Preferably, a powder obtained by mixing and granulating one or more additives selected from the above excipients, disintegrants, binders, and sweeteners is added as the rear end, and it is added together with a lubricant. A pharmaceutical composition is obtained by compression. Tableting can be performed using a commercially available tableting machine. The pharmaceutical composition produced by tableting in this manner can take a known dosage form, but is preferably an orally disintegrating tablet.

In addition, uncoated tablets or uncoated granules after granulation may be coated. When coating, it is preferably carried out by means such as a film coating machine, a fluidized bed granulator and the like. Coatings include, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate, cellulose acetate phthalate, aminoalkyl methacrylate copolymer E, Coating agents known in the art such as aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, ethyl acrylate/methyl methacrylate copolymer dispersion, and sucrose are used. be able to.

Specific production examples and test results of the pharmaceutical composition according to the present invention will be shown to explain in more detail.

[Example 1]
Granules were prepared by different addition methods of drug substances during granulation, and tablets containing the granules were produced.

[Example 1A]
80.8 g of edoxaban tosilate hydrate was dispersed in an aqueous solution prepared by dissolving 12 g of hydroxypropylcellulose in 621 g of purified water. The obtained solution was sprayed to a fluidized bed granulator (manufactured by Powrex Co., Ltd.) to carry out fluidized bed granulation, drying and sizing. 4.64 g of the obtained granules, 13.08 g of D-mannitol, 1.68 g of crystalline cellulose, 0.25 g of crospovidone, 0.25 g of carmellose, and 0.10 g of magnesium stearate were mixed and pressed into a single tableting machine ( Ichihashi Seiki Co., Ltd.), and tableted at a weight of 400 mg per tablet to obtain tablets.

[Comparative example]
18 g of hydroxypropylcellulose was dissolved in 552 g of purified water. 80.8 g of edoxaban tosilate hydrate was charged into a fluidized bed granulator (manufactured by Powrex Co., Ltd.), the obtained solution was added, and fluidized bed granulation, drying and sizing were performed. 4.64 g of the obtained granules, 13.08 g of D-mannitol, 1.68 g of crystalline cellulose, 0.25 g of crospovidone, 0.25 g of carmellose, and 0.10 g of magnesium stearate were mixed and pressed into a single tableting machine ( Ichihashi Seiki Co., Ltd.) and tableted at a weight of 400 mg per tablet to obtain tablets.

[elution]
Dissolution was examined by the dissolution test method (paddle method) described in the Japanese Pharmacopoeia 18th edition at 50 rpm. Using 900 mL of pH 6.8 phosphate buffer as the dissolution test liquid, the formulations of Example 1A and Comparative Example were stirred for 120 minutes, and the dissolution rate was measured over time. Table 1 and FIG. 1 show the measurement results of the dissolution rate.

The pharmaceutical composition of the present invention, in which a water-soluble binder was mixed with the dispersion, was found to have superior dissolution properties compared to the comparative example.

[Example 2]
In Example 1A, granules containing different additives were prepared, and tablets containing edoxaban were produced using the granules.

[Example 2A]
80.8 g of edoxaban tosilate hydrate was dispersed in an aqueous solution prepared by dissolving 12 g of hydroxypropylcellulose in 621 g of purified water. 52.6 g of D-mannitol was put into a fluidized bed granulator (manufactured by Powrex Co., Ltd.), the resulting solution was added, and fluidized bed granulation, drying and sizing were carried out. 7.27 g of the resulting granules, 10.46 g of D-mannitol, 1.68 g of crystalline cellulose, 0.25 g of crospovidone, 0.25 g of carmellose, and 0.10 g of magnesium stearate were mixed and pressed into a single tableting machine ( Ichihashi Seiki Co., Ltd.), and tableted at a weight of 400 mg per tablet to obtain tablets.

[Example 2B]
80.8 g of edoxaban tosilate hydrate was dispersed in an aqueous solution prepared by dissolving 12 g of hydroxypropylcellulose in 621 g of purified water. 26.3 g of D-mannitol and 26.3 g of ethyl cellulose were charged into a fluidized bed granulator (manufactured by Powrex Co., Ltd.), the obtained solution was added, and fluidized bed granulation, drying and sizing were performed. 7.27 g of the resulting granules, 10.46 g of D-mannitol, 1.68 g of crystalline cellulose, 0.25 g of crospovidone, 0.25 g of carmellose, and 0.10 g of magnesium stearate were mixed and pressed into a single tableting machine ( Ichihashi Seiki Co., Ltd.), and tableted at a weight of 400 mg per tablet to obtain tablets.

[Disintegration test]
The disintegration property was examined by the disintegration test method described in the 18th revision of the Japanese Pharmacopoeia. Using water as the test liquid, the formulations of Examples 1A, 2A and 2B were evaluated. Table 2 shows the disintegration test results.

Compared to Examples 1A and 2A, the formulation of Example 2B containing a water-insoluble polymer exhibited superior disintegration properties.

The present invention is summarized as follows.

1. A pharmaceutical composition according to the present invention comprises a granule containing (A) edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (B) a water-soluble binder, comprising an organic The granules containing no acid are granules wet granulated using a dispersion of (A) and (B).

2. 1. The water-soluble binder is one or more binders selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol (partially saponified product), pullulan, starch, dextrin, and gelatin. pharmaceutical composition of

3. (B) The pharmaceutical composition according to 1, wherein the water-soluble binder is one or more binders selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol (partially saponified product).

4. (B) The pharmaceutical composition according to 1, wherein the water-soluble binder is hydroxypropylcellulose.

5. 5. The pharmaceutical composition according to any one of 1 to 4, wherein the granule further contains (C) a powder additive.

6. 6. The pharmaceutical composition according to any one of 1 to 5, wherein the granule is wet granulated using the dispersion and the powder additive.

7. 7. Pharmaceutical composition according to 5 or 6, wherein the powder additive is an excipient.

8. 7. The pharmaceutical composition according to 5 or 6, wherein the powder additive is a mixture of an excipient and a water-insoluble polymer and/or inorganic substance.

9. The water-insoluble polymer and/or inorganic material is cellulose acetate, ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, vinyl acetate resin, magnesium carbonate, calcium carbonate, magnesium aluminometasilicate, magnesium aluminosilicate, silica. 9. The pharmaceutical composition according to 8, which is at least one compound selected from the group consisting of calcium phosphate, magnesium silicate, talc, magnesium oxide, magnesium hydroxide, calcium hydrogen phosphate hydrate, and anhydrous calcium hydrogen phosphate. .

10. 9. The pharmaceutical composition according to 8, wherein the water-insoluble polymer and/or inorganic substance is ethylcellulose.

11. The excipient is at least one selected from the group consisting of crystalline cellulose, starches, sugars, sugar alcohols, light anhydrous silicic acid, talc, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydrogen phosphate, and tribasic calcium phosphate. 11. The pharmaceutical composition according to any one of 7 to 10, which is

12. 11. The pharmaceutical composition according to any one of 7-10, wherein the excipient is a sugar alcohol.

13. (A) 10 to 40 parts by weight of edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof per 100 parts by weight of the entire pharmaceutical composition; The pharmaceutical composition according to any one of 1 to 12, containing 0.1 to 10 parts by weight per 100 parts by weight of the composition.

14. (A) 10 to 40 parts by weight of edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof per 100 parts by weight of the entire pharmaceutical composition; 8. The medicament according to 7, containing 0.1 to 10 parts by weight with respect to 100 parts by weight of the composition, and containing 0.1 to 30 parts by weight of the excipient with respect to 100 parts by weight of the pharmaceutical composition. Composition.

15. (A) Pharmaceutical composition 100 containing 10 to 40 parts by weight of edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof per 100 parts by weight of the pharmaceutical composition, and a water-soluble binder Containing 0.1 to 10 parts by weight per part by weight, containing 0.1 to 30 parts by weight of excipients per 100 parts by weight of the pharmaceutical composition, water-insoluble polymer and / or inorganic substance 9. The pharmaceutical composition according to 8, containing 0.1 to 20 parts by weight per 100 parts by weight of the pharmaceutical composition.

16. (A) The pharmaceutical composition according to any one of 1 to 15, wherein the edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof is edoxaban tosilate hydrate.

17. 17. The pharmaceutical composition according to any one of 1 to 16, which is in the form of an orally disintegrating tablet.

18. (A) preparing a dispersion of edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof and (B) a water-soluble binder; 18. A method of making a pharmaceutical composition according to any one of 1 to 17, comprising the step of forming

It should be considered that the embodiments and examples disclosed above are illustrative in all respects and not restrictive. The scope of the present invention is defined by the scope of the claims rather than the above-described embodiments and examples, and includes all modifications and variations within the scope and meaning equivalent to the scope of the claims.

Claims (18)

(A) edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(B) a granule containing a water-soluble binder;
The granules are granules obtained by wet granulation using the dispersion of (A) and (B),
A pharmaceutical composition that does not contain an organic acid. The water-soluble binder (B) is one or more binders selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol (partially saponified product), pullulan, starch, dextrin, and gelatin. 1. The pharmaceutical composition according to 1. 2. The pharmaceutical composition according to claim 1, wherein the (B) water-soluble binder is one or more binders selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol (partially saponified product). 2. The pharmaceutical composition according to claim 1, wherein (B) the water-soluble binder is hydroxypropylcellulose. The pharmaceutical composition according to any one of claims 1 to 4, wherein the granule further contains (C) a powder additive. 6. The pharmaceutical composition according to claim 5, wherein the granules are wet-granulated using the dispersion and powder additives. 7. The pharmaceutical composition according to claim 5 or 6, wherein said powder additive is an excipient. 7. The pharmaceutical composition according to claim 5 or 6, wherein the powder additive is a mixture of an excipient and a water-insoluble polymer and/or inorganic substance. The water-insoluble polymer and/or inorganic material is cellulose acetate, ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, vinyl acetate resin, magnesium carbonate, calcium carbonate, magnesium aluminometasilicate, magnesium aluminometasilicate, 9. The compound according to claim 8, which is at least one compound selected from the group consisting of calcium silicate, magnesium silicate, talc, magnesium oxide, magnesium hydroxide, calcium hydrogen phosphate hydrate, and anhydrous calcium hydrogen phosphate. pharmaceutical composition. 9. The pharmaceutical composition according to claim 8, wherein said water-insoluble polymer and/or inorganic substance is ethylcellulose. The excipient is at least selected from the group consisting of crystalline cellulose, starches, sugars, sugar alcohols, light anhydrous silicic acid, talc, magnesium oxide, magnesium carbonate, calcium carbonate, calcium hydrogen phosphate, and tribasic calcium phosphate. 11. The pharmaceutical composition according to any one of claims 7-10, which is one. 11. The pharmaceutical composition according to any one of claims 7-10, wherein said excipient is a sugar alcohol. containing 10 to 40 parts by weight of (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof per 100 parts by weight of the entire pharmaceutical composition;
The pharmaceutical composition according to any one of claims 1 to 12, wherein the (B) water-soluble binder is contained in an amount of 0.1 to 10 parts by weight per 100 parts by weight of the pharmaceutical composition. containing 10 to 40 parts by weight of (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof per 100 parts by weight of the entire pharmaceutical composition;
Containing 0.1 to 10 parts by weight of the water-soluble binder (B) with respect to 100 parts by weight of the pharmaceutical composition,
The pharmaceutical composition according to claim 7, comprising 0.1 to 30 parts by weight of the excipient with respect to 100 parts by weight of the pharmaceutical composition. containing 10 to 40 parts by weight of (A) edoxaban, a pharmacologically acceptable salt thereof, or a solvate thereof per 100 parts by weight of the pharmaceutical composition;
The water-soluble binder contains 0.1 to 10 parts by weight with respect to 100 parts by weight of the pharmaceutical composition,
0.1 to 30 parts by weight of the excipient with respect to 100 parts by weight of the pharmaceutical composition,
9. The pharmaceutical composition according to claim 8, which contains 0.1 to 20 parts by weight of the water-insoluble polymer and/or inorganic substance with respect to 100 parts by weight of the pharmaceutical composition. The medicament according to any one of claims 1 to 15, wherein (A) edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof is edoxaban tosilate hydrate. Composition. 17. The pharmaceutical composition according to any one of claims 1 to 16, which is in the form of an orally disintegrating tablet. preparing a dispersion of (A) edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof, and (B) a water-soluble binder;
and forming granules by wet granulation with said dispersion.

Images