JP7629290B2 - Edoxaban-containing granules and orally disintegrating tablets - Google Patents

Description

The present invention relates to an edoxaban-containing granule and an orally disintegrating tablet having improved dissolution properties.

Edoxaban is a selective direct-acting factor Xa inhibitor that exhibits strong inhibitory effect on activated blood coagulation factor X and is useful as a medicine, particularly as an activated blood coagulation factor X inhibitor, a prophylactic and/or therapeutic agent for blood coagulation factors, thrombus or embolism, particularly as a prophylactic and therapeutic agent for thromboembolic diseases (Patent Document 1).

Edoxaban is an active ingredient and is sold as a pharmaceutical formulation under the names "Lixiana (registered trademark) Tablets" and "Lixiana (registered trademark) OD Tablets" (Daiichi Sankyo Co., Ltd.). In addition, the pharmaceutical package insert for the OD tablets states that the OD tablets contain fumaric acid (Non-Patent Document 1).

On the other hand, Patent Document 2, which may be related to "Lixiana (registered trademark) OD tablets" as a formulation containing edoxaban as an active ingredient, describes an invention relating to an orally disintegrating tablet that contains edoxaban and an organic acid and has high disintegrability and dissolution properties in water.

Furthermore, Patent Document 3 describes an invention relating to a method for improving the dissolution of edoxaban, which relates to a method for producing an edoxaban-containing granulated material, the method comprising a step of granulating edoxaban, one or more excipients selected from the group consisting of sugar alcohols and water-swellable additives, a disintegrant, and a binder under conditions in which the maximum moisture value of the granulated material during granulation is maintained at 10% or less.

However, there is no description of a drug-containing granule containing edoxaban and one or more organic acids selected from the group consisting of succinic acid, tartaric acid, citric acid, and glucono-δ-lactone organic acid, nor of an orally disintegrating tablet containing such a drug-containing granule.

WO 03/000657 International Publication No. 2018/101373 Patent No. 5390014

Package insert "Lixiana OD Tablets 15mg/30mg/60mg", revised in January 2018 (3rd edition)

An object of the present invention is to provide a drug-containing granule containing edoxaban that exhibits good dissolution properties, and an orally disintegrating tablet containing the drug granule.

The present inventors have confirmed that a specific organic acid has the desired effect of the present invention from the viewpoint of improving dissolution property, and have thus completed the present invention.

That is, the present invention is as follows:
(1) A drug-containing granule comprising edoxaban, a pharmacologically acceptable salt thereof, or a hydrate thereof, and one or more organic acids selected from the group consisting of succinic acid, tartaric acid, citric acid, and glucono-δ-lactone organic acid;
(2) The drug-containing granule according to (1) above, wherein the organic acid is one or more components selected from the group consisting of succinic acid, tartaric acid, and citric acid.
(3) The drug-containing granule according to any one of (1) to (2), wherein the amount of the organic acid is 0.1 to 30% per 100 parts by mass of edoxaban.
(4) The drug-containing granule according to (1) above, wherein the edoxaban, a pharmacologically acceptable salt thereof, or a hydrate thereof is edoxaban tosilate hydrate.
(5) An orally disintegrating tablet comprising the drug-containing granule according to any one of (1) to (4).
Regarding.

According to the present invention, it is possible to provide a drug-containing granule containing edoxaban, which shows good dissolution properties of edoxaban, and an orally disintegrating tablet containing the drug granule.

FIG. 1 shows the dissolution profiles of edoxaban over time from the formulations in Examples 5 to 8-2 and Comparative Example 2.

The drug-containing particles containing edoxaban and the orally disintegrating tablet of the present invention are described below.

The edoxaban used in the present invention has 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, and edoxaban tosilate hydrate in particular is already used clinically as a medicine and is easily available. The form of edoxaban tosilate hydrate may be either a crystalline state or an amorphous state.

The efficacy and effects are prevention of the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, treatment and prevention of recurrence of venous thromboembolism (deep vein thrombosis and pulmonary embolism), and prevention of the onset of venous thromboembolism in patients undergoing lower limb orthopedic surgery, such as total knee replacement, total hip replacement, or hip fracture surgery.

The amount of edoxaban added is not particularly limited as long as it is the amount of edoxaban in the formulation that constitutes the dosage of the pharmaceutical formulation, for example, 5 to 30% and 10 to 20% of the total amount of the tablet in one embodiment.

The organic acid used in the present invention is not particularly limited as long as it improves the dissolution of edoxaban. Specifically, for example, succinic acid, tartaric acid, citric acid, glucono-δ-lactone organic acid in one embodiment, succinic acid, tartaric acid, citric acid in another embodiment, and succinic acid and citric acid in another embodiment can be mentioned. The glucono-δ-lactone organic acid used in the present invention gradually changes to glucuronic acid when dissolved in water. The amount of the organic acid is not particularly limited as long as it improves the dissolution of edoxaban. For example, the amount of the organic acid is 0.1 to 30% relative to 100 parts by mass of edoxaban in one embodiment, 0.5 to 20% in one embodiment, and 1 to 15% in one embodiment, based on the total amount of the drug-containing granules or tablets.

The drug-containing granules of the present invention may be prepared by using edoxaban, an organic acid, and, if necessary, additives such as excipients, according to a known granulation method such as high-speed stirring granulation or fluidized bed granulation.

In this specification, "good dissolution" means that the dissolution rate is equal to or higher than that of a commercially available preparation. The dissolution rate of edoxaban from the orally disintegrating tablet of the present invention can be evaluated, for example, by the dissolution test method described in the Japanese Pharmacopoeia. Specifically, for example, when a dissolution test is performed using the paddle method at 50 revolutions per minute, the dissolution rate of edoxaban in a dissolution test solution of pH 6.8 is specified to be 60% or more 30 minutes after the start of the dissolution test. In addition, it is specified to be 70% or more 30 minutes after the start of the dissolution test and 80% or more 60 minutes after the start of the dissolution test.

The drug-containing granule of the present invention contains at least one pharmaceutical additive, such as a filler or a binder.

The orally disintegrating tablet of the present invention further comprises one or more pharmaceutical additives selected from the group consisting of excipients, disintegrants, and lubricants.

Examples of excipients include D-mannitol, D-sorbitol, lactose hydrate, sucrose, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropylcellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

Examples of binders include gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and the like.

Examples of disintegrants include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, and crospovidone.

Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hardened oil, sucrose fatty acid esters, and the like.

The blending amount is not particularly limited as long as it does not affect the achievement of the desired effects of the present invention.

The drug-containing granules of the present invention and the orally disintegrating tablets containing the drug-containing granules are formulated by appropriately using various other pharmaceutical additives within the scope of achieving the desired effects of the present invention. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutical and pharmacologically acceptable. For example, surfactants, acidulants, foaming agents, sweeteners, flavorings, colorants, buffers, antioxidants, etc. may be used.

Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

Examples of acidulants include citric acid, tartaric acid, malic acid, etc.

The foaming agent may, for example, be sodium bicarbonate.

Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

Examples of the flavoring include lemon, lemon lime, orange, menthol, and the like.

Examples of coloring agents include ferric oxide, yellow ferric oxide, black ferric oxide, titanium oxide, talc, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, Food Blue No. 3, and the like.

Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or a salt thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or a salt thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or a salt thereof, and the like.

Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, and propyl gallate.

The blending amount is not particularly limited as long as it does not affect the achievement of the desired effects of the present invention.

The drug-containing granule of the present invention can be produced by a method known per se, including steps of milling, mixing, granulation, drying, etc. In detail, the drug-containing granule of the present invention is prepared by mixing edoxaban (which may be milled in advance), an excipient (e.g., D-mannitol), and a binder (e.g., hydroxypropyl cellulose, etc.), followed by stirring and granulation, and then drying and sizing the granules.

The orally disintegrating tablet of the present invention is produced by mixing the drug-containing granulated product of the present invention with an excipient (e.g., D-mannitol), a binder (e.g., hydroxypropylcellulose, etc.), a disintegrant (e.g., partially pregelatinized starch, crospovidone, etc.), and a lubricant (e.g., sodium stearyl fumarate, etc.), mixing, stirring and granulating the granulated product, adding a sweetener (e.g., sucralose, etc.), a lubricant (e.g., magnesium stearate, etc.), mixing, and compressing the mixture (e.g., tableting). Furthermore, the orally disintegrating tablet is coated with a coating agent (e.g., hypromellose, etc.) to produce a film-coated orally disintegrating tablet. The step of blending edoxaban may be any step in the granulation step, such as a mixing step, a step of preparing a binder solution, or a step of adding a disintegrant and a lubricant to the granulated product and mixing them.

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

Edoxaban tosilate hydrate 4.04 g (3.0 g as edoxaban), D-mannitol (PEARLITOL 50C, manufactured by Roquette) 8.74 g, and succinic acid 0.2 g were mixed, and then a binder solution prepared by dissolving hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) 0.02 g in purified water 1 g was added dropwise to the mixture for granulation. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve with 0.85 mm openings to obtain a drug-containing sized powder (drug-containing granulated product of the present invention).

Edoxaban tosilate hydrate 4.04 g (3.0 g as edoxaban), D-mannitol (PEARLITOL 50C, manufactured by Roquette) 8.74 g, and tartaric acid 0.2 g were mixed, and a binder solution prepared by dissolving hydroxypropylcellulose (HPC-SSL, Nippon Soda) 0.02 g in purified water 1 g was added dropwise to the mixture for granulation. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve with 1.0 mm openings to obtain a drug-containing sized powder (drug-containing granulated product of the present invention).

Edoxaban tosilate hydrate 4.04 g (3.0 g as edoxaban), D-mannitol (PEARLITOL 50C, manufactured by Roquette) 8.74 g, and citric acid 0.2 g were mixed, and then a binder solution prepared by dissolving hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) 0.02 g in purified water 1 g was added dropwise to the mixture for granulation. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve with 1.0 mm openings to obtain a drug-containing sized powder (drug-containing granulated product of the present invention).

Edoxaban tosilate hydrate 4.04 g (3.0 g as edoxaban), D-mannitol (PEARLITOL 50C, manufactured by Roquette) 8.74 g, and glucono-δ-lactone organic acid 0.2 g were mixed, and then a binder solution prepared by dissolving hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) 0.02 g in purified water 1 g was added dropwise to the mixture for granulation. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve with 1.0 mm openings to obtain a drug-containing sized powder (drug-containing granulated product of the present invention).

After mixing 2.02 g of edoxaban tosilate hydrate (1.5 g as edoxaban) and 4.27 g of D-mannitol (PEARLITOL 50C, manufactured by Roquette), a binder solution prepared by dissolving 0.01 g of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) and 0.2 g of glucono-δ-lactone organic acid in 1 g of purified water was added dropwise to the mixture for granulation. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve with 1.0 mm openings to obtain a drug-containing sized powder (drug-containing granulated product of the present invention).

Comparative Example 1
Edoxaban tosilate hydrate 4.04 g (3.0 g as edoxaban) and D-mannitol (PEARLITOL 50C, manufactured by Roquette) 8.74 g were mixed, and a binder solution prepared by dissolving 0.02 g of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) in 1 g of purified water was added dropwise to the mixture for granulation. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve with 1.0 mm openings to obtain a drug-containing sized powder (drug-containing granulated product of a comparative example not containing an organic acid).

The amounts of organic acids blended per 100 parts by mass of edoxaban in the drug-containing granules obtained in Examples 1 to 4-2 and Comparative Example 1 are shown in Table 1.

Test Example 1: Dissolution test (Drug-containing granules)
Dissolution tests were performed using 130 mg of the drug-containing granules obtained in Examples 1 to 4 and 128 mg of the drug-containing granules obtained in Comparative Example 1. Dissolution of the drug-containing granules was performed in 900 mL of pH 6.8 buffer solution at 50 rpm using the paddle method in a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.). 20 mL of samples were withdrawn over time from the start of the test until 60 minutes had elapsed, and filtered through a membrane filter with a pore size of 0.45 μm. The dissolution rate of the filtrate was calculated from the absorbance at a wavelength of 260 nm by UV measurement. The measurement results are shown in Table 2.

The results in Table 2 clearly demonstrate that the use of each of the organic acids used in Examples 1 to 4 increases the solubility of the drug.

(Preparation of drug-free granules)
Using a fluidized bed granulation dryer (Powrex: FM-MP-01), 336 g of D-mannitol (Roquette: PEARLITOL 50C), 168 g of crystalline cellulose (Asahi Kasei: KG-1000), and 32 g of crospovidone (BASF Japan: Kollidon CL-F) were mixed and sprayed with a binder solution prepared by dispersing 24 g of alpha-starch (Asahi Kasei: PD-1) in 276 g of purified water to granulate and dry the mixture. After drying, the mixture was sieved through a sieve with 0.71 mm openings to obtain drug-free granules.
(Preparation of orally disintegrating tablets)
To 6.5 g of the drug-containing granules and 3.35 g of the drug-free granules obtained in Example 1, 0.05 g of sucralose (San-Ei Gen F.F.I.: sucralose (P)), 0.002 g of ferric oxide (Venator: ferric oxide), and 0.1 g of sodium stearyl fumarate (JRS Pharma: PRUV) were added and mixed to prepare a powder for tableting, and magnesium stearate (Taihei Chemical Industry: magnesium stearate (vegetable)) was added externally, followed by tableting to obtain orally disintegrating tablets of the present invention as circular tablets with a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
To 6.5 g of the drug-containing granules obtained in Example 2 and 3.35 g of the drug-free granules prepared in Example 5, 0.05 g of sucralose (San-Ei Gen F.F.I.: sucralose (P)), 0.002 g of ferric oxide (Venator: ferric oxide), and 0.1 g of sodium stearyl fumarate (JRS Pharma: PRUV) were added and mixed to prepare a tablet powder, and magnesium stearate (Taihei Chemical Industry: magnesium stearate (vegetable)) was added externally, followed by tableting to obtain orally disintegrating tablets of the present invention as circular tablets with a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
To 6.5 g of the drug-containing granules obtained in Example 3 and 3.35 g of the drug-free granules prepared in Example 5, 0.05 g of sucralose (San-Ei Gen F.F.I.: sucralose (P)), 0.002 g of ferric oxide (Venator: ferric oxide), and 0.1 g of sodium stearyl fumarate (JRS Pharma: PRUV) were added and mixed to prepare a powder for tableting, and magnesium stearate (Taihei Chemical Industry: magnesium stearate (vegetable)) was added externally, followed by tableting to obtain orally disintegrating tablets of the present invention as circular tablets with a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
To 6.5 g of the drug-containing granules obtained in Example 4 and 3.35 g of the drug-free granules prepared in Example 5, 0.05 g of sucralose (San-Ei Gen F.F.I.: sucralose (P)), 0.002 g of ferric oxide (Venator: ferric oxide), and 0.1 g of sodium stearyl fumarate (JRS Pharma: PRUV) were added and mixed to prepare a tablet powder, and magnesium stearate (Taihei Chemical Industry: magnesium stearate (vegetable)) was added externally, followed by tableting to obtain orally disintegrating tablets of the present invention as circular tablets with a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
0.025 g of sucralose (San-Ei Gen F.F.I.: sucralose (P)), 0.001 g of ferric oxide (Venator: ferric oxide), and 0.05 g of sodium stearyl fumarate (JRS Pharma: PRUV) were added to 3.25 g of the drug-containing granules obtained in Example 4-2 and 1.675 g of the drug-free granules prepared in Example 5, and mixed to prepare a tablet powder. Magnesium stearate (Taihei Chemical Industry: magnesium stearate (vegetable)) was added externally, and tableting was performed to obtain orally disintegrating tablets of the present invention as circular tablets with a tablet mass of 200 mg and a diameter of 8 mm.

Comparative Example 2
(Preparation of orally disintegrating tablets)
To 3.2 g of the drug-containing granules obtained in Comparative Example 2 and 1.675 g of the drug-free granules prepared in Example 5, 0.05 g of D-mannitol (manufactured by Roquette: PEARITOL 50C), 0.025 g of sucralose (manufactured by San-Ei Gen F.F.I.: sucralose (P)), 0.001 g of ferric oxide (manufactured by VENATOR: ferric oxide), and 0.05 g of sodium stearyl fumarate (manufactured by JRS Pharma: PRUV) were added and mixed to prepare a tablet powder, and magnesium stearate (manufactured by Taihei Chemical Industry: magnesium stearate (vegetable)) was added externally, followed by tableting to obtain orally disintegrating tablets of Comparative Example containing no organic acid as circular tablets with a tablet mass of 200 mg and a diameter of 8 mm.

The amounts of ingredients in the orally disintegrating tablets obtained in Examples 5 to 8-2 and Comparative Example 2 are shown in Table 3 (unit: mg).

Test Example 2: Dissolution test (orally disintegrating tablet)
Dissolution tests were conducted using the tablets obtained in Examples 5 to 8-2 and Comparative Example 2. Dissolution of the tablets was conducted in 900 mL of pH 6.8 buffer solution at 50 rpm using a paddle method in a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.). 20 mL of samples were withdrawn over time from the start of the test until 60 minutes had elapsed, and filtered through a membrane filter with a pore size of 0.45 μm. The dissolution rate of the filtrate was calculated from the absorbance at a wavelength of 260 nm by UV measurement. The measurement results are shown in Table 4 and FIG. 1.

In addition, the tablet physical properties (tablet hardness, tablet thickness) and oral disintegration time were measured using the tablets obtained in Examples 5 to 8-2 and Comparative Example 2. The measurement results are shown in Table 5.

1, the dissolution profile shows that the solubility of the drug is increased by the tablets prepared according to the present invention, and the results of Tables 4 and 5 show that Examples 6 and 7 showed good dissolution properties despite having a hardness of 80 N or more. It was also shown that the dissolution rate is not increased simply by having a low tablet hardness and a fast disintegration time.

Claims (4)

A drug-containing granule comprising edoxaban, a pharmacologically acceptable salt thereof, or a hydrate thereof , one or two organic acids selected from the group consisting of tartaric acid and citric acid , and D-mannitol.
An orally disintegrating tablet comprising : The orally disintegrating tablet according to claim 1 , wherein the amount of the organic acid in the drug-containing granules is 0.1 to 30% per 100 parts by mass of edoxaban. The orally disintegrating tablet according to any one of claims 1 to 2 , wherein the edoxaban, a pharmacologically acceptable salt thereof, or a hydrate thereof is edoxaban tosylate hydrate. The orally disintegrating tablet according to any one of claims 1 to 3 , wherein the drug-containing granules further contain hydroxypropyl cellulose .

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