Edoxaban-containing orally disintegrating tablets

Abstract

The objective is to provide an orally disintegrating tablet containing edoxaban with improved dissolution properties in the neutral region. [Solution] To provide granulated granules containing 45% or more edoxaban tosylate hydrate, and orally disintegrating tablets containing pharmaceutical additives and free of organic acids.

Description

Technical Field

[0007] ,

[0001] The present invention relates to an edoxaban-containing orally disintegrating tablet with improved elution properties in the neutral region.

Background Art

[0002] Edoxaban is a selective direct factor Xa inhibitor, showing a strong inhibitory effect on activated blood coagulation factor X, and is useful in pharmaceuticals, particularly in inhibitors of activated blood coagulation factor X, blood coagulation factors, prevention and / or treatment agents for thrombus or embolism, especially in the prevention and treatment of thromboembolic diseases (Patent Document 1).

[0003] There is a pharmaceutical preparation sold (by Daiichi Sankyo Company, Limited) under the name of "Lexiana (registered trademark) tablets" and "Lexiana (registered trademark) OD tablets" with edoxaban as an active ingredient. Also, it is described in the pharmaceutical package insert for the OD tablets that the OD tablets contain fumaric acid (Non-Patent Document 1).

[0004] On the other hand, Patent Document 2 describes an invention related to a tablet containing edoxaban and hydroxypropyl cellulose without containing an organic acid as a preparation with edoxaban as an active ingredient.

[0005] Patent Document 3 also describes an invention related to a tablet containing edoxaban, hydroxypropyl cellulose having a viscosity of 2 to 3 cps at 20°C when prepared in a 2% aqueous solution, lactose, and partially pregelatinized starch without containing an organic acid.

[0006] However, there is no description of an orally disintegrating tablet containing granulated particles with an edoxaban tosylate hydrate content of 45% or more and a pharmaceutical additive without containing an organic acid.

Prior Art Documents

Patent Documents

[0007] [

Patent Document 1

[0008] [Non-Patent Document 1] Package insert for "Lixiana OD Tablets 15mg / 30mg / 60mg," revised January 2018 (3rd edition) [Overview of the project] [Problems that the invention aims to solve]

[0009] The object of the present invention is to provide an edoxaban-containing orally disintegrating tablet with improved dissolution properties in the neutral region. [Means for solving the problem]

[0010] As a result of diligent research, the inventors of this invention discovered that, even without using organic acids, the disintegration time can be shortened by using specific pharmaceutical additives, thereby improving the elution properties in the neutral range, and thus completed the present invention.

[0011] In other words, the present invention is (1) Granulated granules containing 45% or more of edoxaban tosylate hydrate, and orally disintegrating tablets containing pharmaceutical excipients and free of organic acids. (2) The orally disintegrating tablet according to (1) above, wherein the granulated granules contain a binder. (3) The orally disintegrating tablet described in (2) above, wherein the binder contained in the granulated granules is hydroxypropylcellulose. (4) The orally disintegrating tablet according to (3) above, wherein the hydroxypropylcellulose has a viscosity of 6 to 10 mPa·s. (5) Orally disintegrating tablets according to (1) above, wherein the granulated granules contain an excipient. (6) The orally disintegrating tablet according to (5) above, wherein the excipient contained in the granulated granules is D-mannitol. (7) Orally disintegrating tablets according to (1) above, wherein the granulated granules contain a disintegrant. (8) The orally disintegrating tablet according to (7) above, wherein the disintegrant contained in the granulated granules is corn starch. (9) The orally disintegrating tablet according to (1) above, wherein the pharmaceutical excipient is one or more pharmaceutical excipients selected from the group consisting of D-mannitol, low-substituted hydroxypropylcellulose, polyvinyl alcohol (fully hydrolyzed) granules, crospovidone, sucralose, magnesium aluminometasilicate, yellow ferric oxide, ferric oxide, sodium stearyl fumarate, and magnesium stearate. (10) A method for producing the orally disintegrating tablet described in (1) above, Regarding. [Effects of the Invention]

[0012] According to the present invention, it is possible to provide an orally disintegrating tablet containing edoxaban with improved dissolution properties in the neutral region. [Modes for carrying out the invention]

[0013] In this specification, "improved dissolution in the neutral range" means ensuring the same dissolution rate as commercially available edoxaban-containing film-coated tablets. The dissolution rate of edoxaban from the tablets of the present invention can be evaluated, for example, by the dissolution test method described in the Japanese Pharmacopoeia. Specifically, for example, when performing a dissolution test using the paddle method at 50 revolutions per minute, the dissolution rate of edoxaban in a pH 6.8 dissolution test solution is defined as 60% or more 15 minutes after the start of the dissolution test. Furthermore, in the same test, it is defined as 80% or more 90 minutes after the start of the dissolution test. Note that the formulation used as a comparison for the orally disintegrating tablets is a film-coated tablet, and at 5 minutes the tablet has not yet disintegrated, resulting in a low dissolution rate. Since the orally disintegrating tablets of the present invention disintegrate quickly, the dissolution rate is higher than that of the film-coated tablets. Therefore, 90 minutes was set as the point at which similarity with film-coated tablets is determined.

[0014] The following describes the edoxaban-containing orally disintegrating tablets of the present invention.

[0015] As the edoxaban used in the present invention, it is called by the chemical name N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide. In particular, edoxaban tosylate hydrate has already been clinically used as a medicine and can be easily obtained. The form of edoxaban tosylate hydrate can be used in either a crystalline state or an amorphous state.

[0016] The efficacy and effect are the suppression of the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, the treatment and recurrence suppression of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism), and the suppression of the onset of venous thromboembolism in patients undergoing lower limb orthopedic surgeries such as total knee arthroplasty, total hip arthroplasty, and hip fracture surgery.

[0017] The blending amount is not particularly limited as long as it is an amount of edoxaban. For example, as edoxaban tosylate hydrate, in some embodiments in the granulated product, it is 45% by weight or more, in some embodiments 79% by weight or more, and in some embodiments 9%6% by weight or more.

[0018] The pharmaceutical additives used in the present invention are not particularly limited as long as they can achieve the object of the present invention. For example, excipients, binders, disintegrants, lubricants, etc. can be mentioned.

[0019] Examples of excipients include D-mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol (fully saponified) granulated product, D-mannitol, D-sorbitol, lactose hydrate, sucrose, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, etc.

[0020] Examples of binders include hydroxypropyl cellulose.

[0021] Examples of hydroxypropyl cellulose include HPC-SSL (viscosity 2-2.9), HPC-SL (viscosity 3-5.9), HPC-L (viscosity 6-10), HPC-M (viscosity 150-400), and HPC-H (viscosity 1000-4000). In one embodiment, HPC-L (viscosity 6-10) is used. The amount blended per granule is 2.5% by weight in one embodiment, 3% by weight in another embodiment, and 5% by weight in another embodiment. The viscosity of hydroxypropyl cellulose refers to the viscosity in a 2% aqueous solution at 20°C.

[0022] Examples of disintegrants include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and crospovidone. In one embodiment, corn starch is used, and in another embodiment, crospovidone is used. The amount of crospovidone per orally disintegrating tablet is 3-7% by weight in one embodiment, 4-6% by weight in another embodiment, and 4.5-5.5% by weight in another embodiment.

[0023] Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hydrogenated oil, and sucrose fatty acid esters.

[0024] Other examples of pharmaceutical additives include surfactants, foaming agents, sweeteners, fragrances, and colorants.

[0025] Examples of surfactants include polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil.

[0026] Examples of foaming agents include baking soda.

[0027] Examples of sweeteners include sucralose, sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, and thaumatin.

[0028] Examples of flavorings include lemon, lemon-lime, orange, and menthol.

[0029] Examples of coloring agents include iron(III) oxide, yellow iron(III) oxide, black iron oxide, titanium dioxide, talc, Yellow No. 4, Yellow No. 5, Red No. 3, Red No. 102, and Blue No. 3.

[0030] The amount used is not particularly limited, as long as it does not affect the achievement of the desired effects of the present invention.

[0031] The granulated granules of the present invention are included in the orally disintegrating tablets in an amount that does not affect the achievement of the desired effect of the present invention. The amount of granulated granules per orally disintegrating tablet is, in one embodiment, 30-45%, in another embodiment, 30-40%, and in another embodiment, 30-35%. The granulated granules can be manufactured by a known method that includes steps such as crushing, mixing, granulation, and drying. Specifically, the granulated granules of the present invention are formulated by spraying a hydroxypropyl cellulose-containing solution onto edoxaban tosylate hydrate (which may be pre-crushed) or edoxaban tosylate hydrate and a pharmaceutical additive, granulating, and then drying and sizing the granules. The edoxaban tosylate hydrate is present in a dispersed state within the granulated granules.

[0032] Furthermore, the orally disintegrating tablets of the present invention are manufactured by mixing granulated granules containing edoxaban tosylate hydrate with excipients (e.g., D-mannitol, low-substituted hydroxypropylcellulose, polyvinyl alcohol (fully hydrolyzed) granules, etc.), disintegrants (e.g., crospovidone, etc.), sweeteners (e.g., sucralose, etc.), fluidizers (e.g., magnesium aluminometasilicate, etc.), lubricants (e.g., sodium stearyl fumarate, etc.), and colorants (e.g., yellow ferric oxide, ferric oxide, etc.), and then compressing the mixture after mixing (e.g., by tableting). In addition, film-coated orally disintegrating tablets are produced by coating the orally disintegrating tablets with a coating agent (e.g., hypromellose, etc.). The process of incorporating edoxaban may be any of the following steps in the granulation process: the mixing step, the preparation of the binder solution, or the addition and mixing step of the disintegrant and lubricant to the granules. [Examples]

[0033] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way to the following examples. [Examples]

[0034] (Edoxaban tosylate hydrate content in granules: 45%) 121.2 g of edoxaban tosylate hydrate and 140.7 g of D-mannitol (Rocket Co., Ltd.: Pairitol 25C) were mixed, and the mixture was granulated in a fluid bed using a binding solution prepared by dissolving 8.1 g of hydroxypropyl cellulose (Nippon Soda Co., Ltd.: HPC-L) in 153.9 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 90 g of the sized granules were mixed with 74.7 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 9.0 g of crospovidone, 1.8 g of sucralose, 1.8 g of magnesium aluminometasilicate, 0.2 g of yellow ferric oxide, and 2.7 g of stearyl sodium fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained. [Examples]

[0035] (Edoxaban tosylate hydrate content in granules: 79%) 202 g of edoxaban tosylate hydrate and 45 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.: Pharmacopoeia Corn Starch White) were mixed, and granulation was performed in a tumbling fluidized bed using a binding solution of 8 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.: HPC-L) dissolved in 152 g of purified water. The resulting granules were sized using a 1.575 mm screen mill. 51 g of the sized granules were mixed with 113.7 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 9.0 g of crospovidone, 1.8 g of sucralose, 1.8 g of magnesium aluminometasilicate, 0.2 g of yellow ferric oxide, and 2.7 g of stearyl sodium fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained. [Examples]

[0036] (Edoxaban tosylate hydrate content in granules: 96%) 242.4 g of edoxaban tosylate hydrate was granulated in a tumbling fluidized bed using a binding solution prepared by dissolving 9.6 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-L) in 182.4 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 42 g of the sized granules were mixed with 122.7 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 9.0 g of crospovidone, 1.8 g of sucralose, 1.8 g of magnesium aluminometasilicate, 0.2 g of yellow ferric oxide, and 2.7 g of stearyl sodium fumarate. Using the mixed granules obtained above, a tablet with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g was obtained by compression molding with a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5). [Examples]

[0037] (Edoxaban tosylate hydrate content in granules: 50%) 101.0 g of edoxaban tosylate hydrate and 97.0 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences: Mannit P) were mixed, and granulation was performed in a fluid bed using a binding solution prepared by dissolving 4.5 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-L) in 211.5 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 40.5 g of the sized granules were mixed with 42.65 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 4.5 g of crospovidone, 0.9 g of sucralose, 0.1 g of yellow ferric oxide, and 1.35 g of sodium stearyl fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained. [Examples]

[0038] (Edoxaban tosylate hydrate content in granules: 50%) 161.6 g of edoxaban tosylate hydrate and 43.6 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences: Mannit P) were mixed, and granulation was performed in a fluid bed using a binding solution prepared by dissolving 10.8 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-L) in 205.2 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 27.0 g of the sized granules were mixed with 56.15 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 4.5 g of crospovidone, 0.9 g of sucralose, 0.1 g of yellow ferric oxide, and 1.35 g of stearyl sodium fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained. [Examples]

[0039] (Edoxaban tosylate hydrate content in granules: 75%) 161.6 g of edoxaban tosylate hydrate and 43.6 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences: Mannit P) were mixed, and granulation was performed in a fluid bed using a binding solution prepared by dissolving 10.8 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-L) in 205.2 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 27.0 g of the sized granules were mixed with 54.35 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 6.3 g of crospovidone, 0.9 g of sucralose, 0.1 g of yellow ferric oxide, and 1.35 g of stearyl sodium fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained. [Examples]

[0040] (Edoxaban tosylate hydrate content in granules: 75%) 161.6 g of edoxaban tosylate hydrate and 43.6 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences: Mannit P) were mixed, and granulation was performed in a fluid bed using a binding solution prepared by dissolving 10.8 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-L) in 205.2 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 27.0 g of the sized granules were mixed with 57.95 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 2.7 g of crospovidone, 0.9 g of sucralose, 0.1 g of yellow ferric oxide, and 1.35 g of sodium stearyl fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained. [Examples]

[0041] (Edoxaban tosylate hydrate content in granules: 75%) 161.6 g of edoxaban tosylate hydrate and 43.6 g of D-mannitol (manufactured by Mitsubishi Corporation Life Sciences: Mannit P) were mixed, and granulation was performed in a fluid bed using a binding solution prepared by dissolving 10.8 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-L) in 205.2 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 27.0 g of the sized granules were mixed with 56.15 g of D-mannitol, low-substituted hydroxypropyl cellulose, and polyvinyl alcohol (fully saponified) granules, 4.5 g of crospovidone, 0.9 g of sucralose, 0.1 g of yellow ferric oxide, and 1.35 g of stearyl sodium fumarate. By compressing the mixed granules obtained above using a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5), tablets of the present invention with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g were obtained.

[0042] ≪Comparative Example 1≫ (Edoxaban tosylate hydrate content in granules: approximately 24%) 80.8 g of edoxaban tosylate hydrate and 250.4 g of D-mannitol (Rocket Co., Ltd.: Pairitol 25C) were mixed, and the mixture was granulated in a fluid bed using a binding solution prepared by dissolving 5.4 g of hydroxypropyl cellulose (Nippon Soda Co., Ltd.: HPC-L) in 102.6 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 168.3 g of the sized granules were mixed with 9.0 g of crospovidone and 2.7 g of stearyl sodium fumarate. Using the mixed granules obtained above, a tablet with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g was obtained by compression molding with a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5).

[0043] ≪Comparative Example 2≫ (Binder: Polyvinyl alcohol (partially saponified)) 121.2 g of edoxaban tosylate hydrate and 140.7 g of D-mannitol (Rocket Co., Ltd.: Pairitol 25C) were mixed, and the mixture was granulated in a fluid bed using a binding solution prepared by dissolving 8.1 g of polyvinyl alcohol (partially saponified) (Mitsubishi Chemical Co., Ltd.: Gosenol EG-05) in 153.9 g of purified water. The resulting granules were sized using a Cormill with a screen diameter of 1.575 mm. 90 g of the sized granules were mixed with 74.7 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules, 9.0 g of crospovidone, 1.8 g of sucralose, 1.8 g of magnesium aluminometasilicate, 0.2 g of yellow ferric oxide, and 2.7 g of stearyl sodium fumarate. Using the mixed granules obtained above, a tablet with a diameter of 13.4 × 7.0 mm and a mass of 0.36 g was obtained by compression molding with a rotary tablet press (manufactured by Kikusui Seisakusho; VEL5).

[0044] The formulations for Examples 1-8 and Comparative Examples 1-2 are shown in Tables 1 and 2.

[0045] [Table 1]

[0046] [Table 2]

[0047] 《Test Example 1: Dissolution Test》 Dissolution tests were performed on Examples 1-8, Comparative Examples 1-2, and Reference Example 1 (Daiichi Sankyo: Lixiana® Tablets 60 mg) in accordance with the Japanese Pharmacopoeia dissolution test method. Tablets were dissolved using a dissolution tester (manufactured by Toyama Sangyo) with the paddle method, set to a paddle rotation speed of 50 rpm, and 900 mL of dissolution test solution 2 was used as the test solution. 20 mL of the sample was withdrawn at intervals from the start of the test until 90 minutes later, and immediately replaced with 20 mL of test solution warmed to 37 ± 0.5°C. The samples were filtered through a membrane filter with a pore size of 0.45 μm or less, and the dissolution rate was calculated from the absorbance at a wavelength of 289 nm by HPLC measurement of the filtrate. Table 3 shows the results of the dissolution test. In Comparative Examples 1 and 2, the dissolution rate was lower compared to Reference Example 1. On the other hand, Examples 1 to 8 showed good dissolution rates similar to Reference Example 1.

[0048] [Table 3]

[0049] 《Test Example 2: Collapse Test》 Disintegration tests were conducted on the orally disintegrating tablets of Examples 1, 4-8, and Comparative Example 2, and the disintegration time was evaluated using a disintegration testing machine (manufactured by Toyama Sangyo). The test results are shown in Table 4.

[0050] [Table 4]

Claims

1. Orally disintegrating tablets containing granulated granules with an edoxaban tosylate hydrate content of 45% or more, and pharmaceutical excipients, without organic acids.

2. An orally disintegrating tablet according to claim 1, wherein the granulated granules contain a binder.

3. The orally disintegrating tablet according to claim 2, wherein the binder contained in the granulated granules is hydroxypropylcellulose.

4. The orally disintegrating tablet according to claim 3, wherein the hydroxypropylcellulose has a viscosity of 6 to 10 mPa·s.

5. An orally disintegrating tablet according to claim 1, wherein the granulated granules contain an excipient.

6. The orally disintegrating tablet according to claim 5, wherein the excipient contained in the granulated granules is D-mannitol.

7. An orally disintegrating tablet according to claim 1, wherein the granulated granules contain a disintegrant.

8. The orally disintegrating tablet according to claim 7, wherein the disintegrant contained in the granulated granules is corn starch.

9. An orally disintegrating tablet according to claim 1, wherein the pharmaceutical excipient is one or more pharmaceutical excipients selected from the group consisting of D-mannitol, low-substituted hydroxypropylcellulose, polyvinyl alcohol (fully hydrolyzed) granules, crospovidone, sucralose, magnesium aluminometasilicate, yellow ferric oxide, ferric oxide, sodium stearyl fumarate, and magnesium stearate.

10. A method for producing an orally disintegrating tablet according to claim 1.

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