JP2021063077A - Edoxaban-containing granule and orally disintegrable tablet - Google Patents

Abstract

To provide a chemical-containing granule that contains edoxaban showing excellent leachability, and an orally disintegrable tablet containing the chemical-containing granule.SOLUTION: A chemical-containing granule contains 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. There is also provided an orally disintegrable tablet containing the chemical-containing granule.SELECTED DRAWING: Figure 1

Description

The present invention relates to edoxaban-containing granules and orally disintegrating tablets having improved dissolution.

Edoxaban is a selective direct-acting factor Xa inhibitor that exhibits potent inhibitory activity on activated blood coagulation factor X and is a drug, especially activated blood coagulation factor X inhibitor, blood coagulation factor, thrombus or embolus. It is useful for the prevention and / or therapeutic agent of, particularly for the prevention and treatment of thromboembolic diseases (Patent Document 1).

It is sold as a pharmaceutical preparation containing edoxaban as an active ingredient as "Lixiana (registered trademark) tablets" and "Lixiana (registered trademark) OD tablets" (Daiichi Sankyo Co., Ltd.). Further, the pharmaceutical package insert relating to the OD tablet describes that the OD tablet contains fumaric acid (Non-Patent Document 1).

On the other hand, Patent Document 2, which may be related to "Lixiana (registered trademark) OD tablet" as a preparation containing edoxaban as an active ingredient, describes an oral cavity having both edoxaban and high disintegration into water containing an organic acid and dissolution property. Inventions relating to internally disintegrating tablets are described.

Further, in Patent Document 3, as a method for improving elution of edoxaban, one or more excipients, disintegrants, and binders selected from the group consisting of edoxaban, sugar alcohols, and water-swellable additives are being granulated. Described is an invention relating to a method for producing an edoxaban-containing granule, which comprises a step of granulating under the condition that the maximum moisture value of the granulated product is maintained at 10% or less.

However, drug-containing granules 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 acids, and the said. There is no mention of orally disintegrating tablets containing drug-containing granules.

International Publication No. 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 granulated product containing edoxaban showing good dissolution property and an orally disintegrating tablet containing the drug granulated product.

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

That is, the present invention is as follows:
(1) One or more selected from the group consisting of edoxaban, a pharmacologically acceptable salt thereof, or a hydrate thereof, and an organic acid consisting of succinic acid, tartaric acid, citric acid, and glucono-δ-lactone organic acid. Drug-containing granules containing organic acids,
(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 granulated product according to any one of (1) to (2) above, wherein the blending amount of the organic acid is 0.1 to 30% with respect to 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 an edoxaban tosylate hydrate.
(5) An orally disintegrating tablet containing the drug-containing granulated product according to any one of (1) to (4) above.
Regarding.

According to the present invention, it is possible to provide a drug-containing granulated product containing edoxaban and an orally disintegrating tablet containing the drug granulated product, which exhibits good edoxaban elution.

It is a figure which shows the elution profile of edoxaban with time from the preparations in Examples 5-8-2 and Comparative Example 2.

The drug-containing particles containing edoxaban and the orally disintegrating tablets of the present invention will be described below.

The edoxaban used in the present invention has a chemical name of N'-(5-chloropyridin-2-yl) -N-[(1S, 2R, 4S) -4- (dimethylcarbamoyl) -2-[(5-methyl). -6,7-dihydro-4H- [1,3] thiazolo [5,4-c] pyridin-2-carbonyl) amino] cyclohexyl] oxamide, especially edoxavantosilate hydrate, has already been used as a medicine. It is used clinically and is readily available. The form of edoxavantosilate hydrate can be used in either a crystalline state or an amorphous state.

Indications include suppression of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, treatment and recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism), and total hip fracture. It is the suppression of the onset of venous thromboembolism in patients undergoing lower limb orthopedic surgery such as replacement surgery, total hip joint replacement surgery, and hip fracture surgery.

The blending amount is not particularly limited as long as it is the amount of edoxaban in the preparation constituting the dose as a pharmaceutical preparation. For example, 5 to 30% in some embodiments and 10 to 20% in some embodiments per total tablet volume.

The organic acid used in the present invention is not particularly limited as long as it improves the elution 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 one embodiment, and succinic acid, citric acid in one 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 to be blended is not particularly limited as long as it improves the elution of edoxaban. For example, it is 0.1 to 30% with respect to 100 parts by mass of edoxaban in some embodiments, 0.5 to 20% in some embodiments, and 1 to 15% in some embodiments, based on the total amount of the drug-containing granulated product or tablet. ..

The drug-containing granulated product of the present invention is prepared according to a known granulation method such as a high-speed stirring granulation method or a fluidized bed granulation method using additives such as edoxaban, an organic acid and, if necessary, an excipient. It should be.

As used herein, "good elution" means ensuring an elution rate equal to or higher than that of a commercially available preparation. The dissolution property of edoxaban from the orally disintegrating tablet of the present invention can be evaluated by, for example, the dissolution test method described in the Japanese Pharmacopoeia. Specifically, for example, when the dissolution test is performed at 50 rpm by the paddle method, the dissolution rate of edoxaban in the dissolution test solution having a pH of 6.8 is defined as 60% or more 30 minutes after the start of the dissolution test. Further, it is defined as 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 granules of the present invention contain at least one pharmaceutical additive of an excipient or a binder.

In addition, the orally disintegrating tablet of the present invention contains one or more pharmaceutical additives selected from the group consisting of excipients, disintegrants, and lubricants.

Excipients include, for example, D-mannitol, D-sorbitol, lactose hydrate, sucrose, starch, pregelatinized starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, gum arabic, dextrin, pullulan, etc. Examples thereof include light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

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

Examples of the disintegrant include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium, low-degree-of-substitution hydroxypropyl cellulose, partially pregelatinized starch, crospopidone and the like.

Examples of the lubricant include stearyl fumarate, stearic acid, sodium stearate, talc, magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester and the like.

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

In the drug-containing granules of the present invention and the orally disintegrating tablets containing the drug-containing granules, various further pharmaceutical additives are appropriately used and formulated as long as the desired effects of the present invention are achieved. Will be done. The pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, surfactants, acidulants, foaming agents, sweeteners, flavors, colorants, buffers, antioxidants and the like are used.

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

Examples of the acidulant include citric acid, tartaric acid, malic acid and the like.

Examples of the foaming agent include baking soda and the like.

Examples of the sweetener include sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.

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

Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, iron black oxide, titanium oxide, tartrazine, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible blue No. 3, and the like. Can be mentioned.

As buffers, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or its salts, glutamic acid, glutamic acid, glycine, aspartic acid, alanine, arginine or its salts, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid. , Citric acid or salts thereof and the like.

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

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

The drug-containing granulated product of the present invention can be produced by a method known per se, which includes steps such as pulverization, mixing, granulation, and drying. Specifically, the drug-containing granules of the present invention are mixed with edoxaban (which may be pre-milled), an excipient (eg, D-mannitol), and a binder (eg, hydroxypropyl cellulose, etc.) and then stirred. It is formulated by granulating and drying and sizing the granulated product.

In addition, the orally disintegrating tablet of the present invention is added to the drug-containing granule of the present invention with an excipient (for example, D-mannitol), a binder (for example, hydroxypropyl cellulose, etc.), and a disintegrant (for example, partial alpha). Chemical starch, crospovidone, etc.) and lubricant (for example, sodium stearate fumarate, etc.) are mixed, and after mixing, the granulated product is agitated and granulated, and the granulated product is dried and sized to contain a drug. A granulated product, a sweetener (for example, sclarose, etc.) and a lubricant (for example, magnesium stearate, etc.) are added and mixed, and the mixture is compression-molded (for example, tableted) to produce the mixture. Further, the orally disintegrating tablet is coated with a coating agent (for example, hypromellose) to produce a film-coated orally disintegrating tablet. The step of blending edoxaban may be any of a mixing step, a binder solution preparation step, a disintegrant and a lubricant addition / mixing step, and the like in the granulation step.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

After mixing 4.04 g of edoxaban tosilate hydrate (3.0 g as edoxaban), 8.74 g of D-mannitol (manufactured by Roquette: PEARLITOR 50C) and 0.2 g of succinic acid, hydroxypropyl cellulose (Nippon Soda: HPC) -SSL) A binder solution prepared by dissolving 0.02 g of 0.02 g in 1 g of purified water is added dropwise to granulate. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve having a mesh size of 0.85 mm to obtain a drug-containing sized powder (drug-containing granulated product of the present invention).

After mixing 4.04 g of edoxaban tosilate hydrate (3.0 g as edoxaban), 8.74 g of D-mannitol (manufactured by Roquette: PEARLITOR 50C) and 0.2 g of tartaric acid, hydroxypropyl cellulose (Nippon Soda: HPC-) A binder solution prepared by dissolving 0.02 g of SSL) in 1 g of purified water is added dropwise to granulate. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve having a mesh size of 1.0 mm to obtain a drug-containing granulated powder (drug-containing granulated product of the present invention).

After mixing 4.04 g of edoxabantosilate hydrate (3.0 g as edoxaban), 8.74 g of D-mannitol (manufactured by Roquette: PEARLITOR 50C) and 0.2 g of citric acid, hydroxypropyl cellulose (Nippon Soda: HPC) -SSL) A binder solution prepared by dissolving 0.02 g of 0.02 g in purified water is added dropwise to granulate. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve having a mesh size of 1.0 mm to obtain a drug-containing granulated powder (drug-containing granulated product of the present invention).

Hydroxypropyl cellulose after mixing 4.04 g of edoxavantosilate hydrate (3.0 g as edoxaban), 8.74 g of D-mannitol (manufactured by Roquette: PEARLITOR 50C) and 0.2 g of glucono-δ-lactone organic acid. A binder solution prepared by dissolving 0.02 g of (Nippon Soda: HPC-SSL) in 1 g of purified water is added dropwise to granulate. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve having a mesh size of 1.0 mm to obtain a drug-containing granulated powder (drug-containing granulated product of the present invention).

After mixing 2.02 g of edoxavantosilate hydrate (1.5 g as edoxaban) and 4.27 g of D-mannitol (manufactured by Roquette: PEARLITOR 50C), 0.01 g of hydroxypropyl cellulose (Nippon Soda: HPC-SSL). A binder solution prepared by dissolving 0.2 g of glucono-δ-lactone organic acid in 1 g of purified water is added dropwise to granulate. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve having a mesh size of 1.0 mm to obtain a drug-containing granulated powder (drug-containing granulated product of the present invention).

<< Comparative Example 1 >>
After mixing 4.04 g of edoxaban tosilate hydrate (3.0 g as edoxaban) and 8.74 g of D-mannitol (manufactured by Roquette: PEARLITOR 50C), 0.02 g of hydroxypropyl cellulose (Nippon Soda: HPC-SSL). Is dissolved in 1 g of purified water, and a binder solution is added dropwise to granulate. After completion of granulation, the mixture was dried using a shelf dryer and sieved through a sieve having a mesh size of 1.0 mm to obtain a drug-containing granulated powder (a drug-containing granulated product of a comparative example containing no organic acid). ..

Table 1 shows the blending amount of the organic acid with respect to 100 parts by mass of edoxaban in the drug-containing granules obtained in Examples 1 to 4-2 and Comparative Example 1.

<< Test Example 1: Dissolution test >> (drug-containing granulated product)
An dissolution test was conducted 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. The drug-containing granulated product was dissolved in an dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) by the paddle method at 50 rpm in 900 mL of pH 6.8 buffer. 20 mL of the sample was withdrawn over time from the start of the test to 60 minutes later, filtered through a membrane filter having a pore size of 0.45 μm, and the elution rate of the filtrate was calculated from the absorbance at a wavelength of 260 nm by the UV measurement method. The measurement results are shown in Table 2.

From the results in Table 2, it is clearly demonstrated that the solubility of the drug is enhanced by using each of the organic acids used in Examples 1 to 4.

(Preparation of drug-free granulated product)
Using a fluidized layer granulation dryer (Paurek: FM-MP-01), D-mannitol (Roquette: PEARLITOR 50C) 336 g, crystalline cellulose (Asahi Kasei: KG-1000) 168 g, crospovidone (BASF Japan:: 32 g of Kollidon CL-F) was mixed, and a binder solution in which 24 g of pregelatinized starch (Asahi Kasei: PD-1) was dispersed in 276 g of purified water was sprayed, and after granulation and drying were completed, the opening was 0.71 mm. It was sieved with a sieve to obtain a drug-free granule.
(Preparation of orally disintegrating tablets)
6.5 g of the drug-containing granules obtained in Example 1 and 3.35 g of the drug-free granules, 0.05 g of sucralose (manufactured by Saneigen FFI: sclarose (P)), 0 iron sesquioxide. .002 g (manufactured by VENATOR: iron sesquioxide) and 0.1 g of stearyl sodium fumarate (manufactured by JRS Pharma: PRUV) were added and mixed to prepare a tableting powder, and magnesium stearate (manufactured by Taihei Kagaku Sangyo: stearate) was prepared. Magnesium (vegetable) was externally added and tableted to obtain an orally disintegrating tablet of the present invention as a circular tablet having a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
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 were added with sucralose (manufactured by Saneigen FFI: sclarose (P)) 0. 05 g, 0.002 g of iron sesquioxide (manufactured by VENATOR: iron sesquioxide), and 0.1 g of sodium stearate fumarate (manufactured by JRS Pharma: PRUV) were added and mixed to prepare a tableting powder, and magnesium stearate (Taipei) was prepared. Chemical industry: Magnesium stearate (vegetable) was externally added and tableted to obtain an orally disintegrating tablet of the present invention as a circular tablet having a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
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 were added with sucralose (manufactured by Saneigen FFI: sclarose (P)) 0. 05 g, 0.002 g of iron sesquioxide (manufactured by VENATOR: iron sesquioxide), and 0.1 g of sodium stearate fumarate (manufactured by JRS Pharma: PRUV) were added and mixed to prepare a tableting powder, and magnesium stearate (Taipei) was prepared. Chemical industry: Magnesium stearate (vegetable) was externally added and tableted to obtain an orally disintegrating tablet of the present invention as a circular tablet having a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
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 were added with sucralose (manufactured by Saneigen FFI: sclarose (P)) 0. 05 g, 0.002 g of iron sesquioxide (manufactured by VENATOR: iron sesquioxide), and 0.1 g of sodium stearate fumarate (manufactured by JRS Pharma: PRUV) were added and mixed to prepare a tableting powder, and magnesium stearate (Taipei) was prepared. Chemical industry: Magnesium stearate (vegetable) was externally added and tableted to obtain an orally disintegrating tablet of the present invention as a circular tablet having a tablet mass of 200 mg and a diameter of 8 mm.

(Preparation of orally disintegrating tablets)
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 were sucralose (manufactured by San-Ei Gen FFI: Sclarose (P)). 0.025 g, 0.001 g of iron sesquioxide (manufactured by VENATOR: iron sesquioxide), and 0.05 g of sodium stearate fumarate (manufactured by JRS Pharma: PRUV) were added and mixed to prepare a tablet powder, and magnesium stearate was prepared. (Manufactured by Taihei Kagaku Sangyo: Magnesium stearate (vegetable)) was externally added and tableted to obtain an orally disintegrating tablet of the present invention as a circular tablet having a tablet mass of 200 mg and a diameter of 8 mm.

<< Comparative Example 2 >>
(Preparation of orally disintegrating tablets)
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: PEARITOL50C), and sclarose (Saneigen F). -Mixed by adding 0.025 g of sclarose (P) (manufactured by F.I.), 0.001 g of iron sesquioxide (manufactured by VENATOR: iron sesquioxide), and 0.05 g of sodium stearate fumarate (manufactured by JRS Pharma: PRUV). Preparation of tablet powder, magnesium stearate (manufactured by Taihei Kagaku Sangyo: magnesium stearate (vegetable)) is externally added to perform tableting, and comparison is made as a round tablet with a tablet mass of 200 mg and φ8 mm that does not contain organic acid. An example orally disintegrating tablet was obtained.

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

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

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

From the results of Table 2 and FIG. 1, the dissolution profile shows that the tablets prepared according to the present invention increase the solubility of the drug, and from the results of Tables 4 and 5, the hardness of Examples 6 and 7 is high. Although it was 80 N or more, it showed good dissolution. It was also shown that low tablet hardness and fast disintegration time do not increase the elution rate.

Claims (5)

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 acids. A drug-containing granule containing. The drug-containing granule according to claim 1, wherein the organic acid is one or more components selected from the group consisting of succinic acid, tartaric acid, and citric acid. The drug-containing granulated product according to any one of claims 1 to 2, wherein the amount of the organic acid blended is 0.1 to 30% with respect to 100 parts by mass of edoxaban. The drug-containing granule according to claim 1, wherein the edoxaban, a pharmacologically acceptable salt thereof, or a hydrate thereof is an edoxaban tosilate hydrate. An orally disintegrating tablet containing the drug-containing granulated product according to any one of claims 1 to 4.

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