Orally disintegrating tablets containing apixaban

Abstract

To provide an orally disintegrating tablet containing apixaban that maintains its disintegration properties even after storage. [Solution] A pharmaceutical composition containing the following components (a) and (b). (a) Apixaban or its salt or solvate (b) D-mannitol characterized by having a D90 of 200-400 μm

Description

Technical Field

[0001] The present invention relates to an orally disintegrating tablet containing apixaban.

Background Art

[0002] Apixaban (chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) is a factor Xa inhibitor represented by the following formula (1), and is manufactured and sold as a pharmaceutical having an effect of suppressing the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, and treating and suppressing recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism) (see the attached document of Non-Patent Document 1).

Chemical Formula

[0003] Various studies have been conducted on the formulation of apixaban. For example, Patent Document 1 reports a formulation in which elution is controlled by including amorphous apixaban and a polymer selected from hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose. Further, Patent Document 2 reports an orally disintegrating tablet containing apixaban, which contains an apixaban solid dispersion in which amorphous apixaban is dispersed, with a cellulose-based polymer or a pharmaceutically acceptable acrylic-based polymer as a carrier. Patent Document 3 reports a pharmaceutical composition in which D90 of the contained apixaban is 89 μm or less and has good elution properties. Patent Document 4 reports an apixaban-containing pharmaceutical composition characterized by containing apixaban coated with an aminoalkyl methacrylate copolymer.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

[0005] [Non-Patent Document 1] Eliquis Tablets Package Insert, Revised November 2023 (5th Edition) [Overview of the project] [Problems that the invention aims to solve]

[0006] To improve administration, there is a need for apixaban-containing preparations that are easy to take for the elderly and patients with difficulty swallowing, and that can be taken without water, specifically as orally disintegrating tablets.

[0007] Furthermore, when dispensing medications, if a patient is taking multiple drugs, efforts are often made to improve medication adherence by packaging them in single doses. As a result, the time between when the medication is removed from its packaging or PTP sheet and when the patient takes it becomes longer, increasing the likelihood of it being exposed to unfavorable conditions for drug storage. Under such conditions, orally disintegrating tablets may lose their properties due to changes in their disintegration time.

[0008] The problem that this invention aims to solve is to provide an orally disintegrating tablet containing apixaban that can maintain its disintegration properties even after storage. [Means for solving the problem]

[0009] The inventors of this invention conducted extensive research on apixaban-containing orally disintegrating tablets and discovered that by incorporating 200-400 μm of mannitol into D90, they were able to obtain apixaban-containing orally disintegrating tablets that maintain their disintegration properties even after storage, thus completing the present invention.

[0010] In other words, the present invention is as follows <1> ~ <3> This concerns... <1> An orally disintegrating tablet characterized by containing (a) apixaban or a salt or solvate thereof, and (b) D-mannitol, wherein the D90 of (b) D-mannitol is 200 to 400 μm. <2> (a) Apixaban or a salt or solvate thereof, and (b) D-mannitol are contained within the granules. <1> The orally disintegrating tablets described. <3> Characterized by containing partially pregelatinized starch within the granules. <1> or <2> Orally disintegrating tablets as described above. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide an apixaban-containing orally disintegrating tablet that can maintain its disintegration properties even after storage. [Modes for carrying out the invention]

[0012] [Orally disintegrating tablets] The orally disintegrating tablet of the present invention is characterized by containing (a) apixaban or a salt or solvate thereof, and (b) D-mannitol, wherein the D90 of (b) D-mannitol is 200 to 400 μm.

[0013] (Component (a)) [ka] Apixaban is a compound represented by the following formula (1).

[0014] In the present invention, apixaban includes, in addition to the free form of apixaban, its pharmaceutically acceptable salts and their solvates, with the free form of apixaban being preferred.

[0015] Also, apixaban may be amorphous or crystalline, with the crystalline form being preferred.

[0016] The D90 in the case of crystals is not particularly limited, but from the viewpoints of fluidity, handling properties, etc., 50 - 500 μm is preferred, 90 - 200 μm is more preferred, and 100 - 150 μm is particularly preferred.

[0017] In the present invention, particle sizes such as D90 and D50 can be measured using the laser diffraction method.

[0018] In the present invention, apixaban is preferably contained inside the granules, and more preferably contained only inside the granules.

[0019] The content of apixaban is preferably 0.5 - 10% by mass, more preferably 1 - 7% by mass, and even more preferably 2 - 5% by mass with respect to the total mass of the orally disintegrating tablets of the present invention.

[0020] The content of apixaban is preferably 1 - 20% by mass, more preferably 2 - 15% by mass, and even more preferably 5 - 10% by mass with respect to the total mass of the granules.

[0021] In this specification, "granules" refers to granulated products or sized products.

[0022] When the granules are included in the present invention, their mass is preferably 10 - 90% by mass, more preferably 20 - 75% by mass, and even more preferably 30 - 45% by mass with respect to the total mass of the orally disintegrating tablets of the present invention.

[0023] The content of apixaban per tablet is not particularly limited, and the dosage used clinically can be appropriately selected. Specifically, in terms of the free form, it is usually 0.05 - 20 mg, preferably 0.05 - 10 mg, and more preferably 2.5 - 5 mg. (ingredient (b))

[0024] In the present invention, D-mannitol is preferably contained within the granules from the viewpoint of solubility and disintegration.

[0025] The D90 of D-mannitol used in the present invention is 200 to 400 μm, preferably 200 to 300 μm, and more preferably 200 to 270 μm, from the viewpoint of changes in disintegration after storage.

[0026] The D50 of D-mannitol used in the present invention is preferably 50 to 500 μm, more preferably 120 to 300 μm, and even more preferably 120 to 180 μm, from the viewpoint of changes in disintegration after storage.

[0027] The D-mannitol content used in the present invention is preferably 30 to 90% by mass, more preferably 50 to 85% by mass, and even more preferably 60 to 80% by mass, relative to the total mass of the orally disintegrating tablets of the present invention, from the viewpoint of disintegration properties and other factors.

[0028] The D-mannitol content used in the present invention is preferably 30 to 95% by mass, more preferably 50 to 90% by mass, and even more preferably 60 to 80% by mass, relative to the total mass of the granules of the present invention, from the viewpoint of disintegration properties and other factors.

[0029] The present invention may further contain partially pregelatinized starch.

[0030] The partially pregelatinized starch used in this invention contributes to solubility and disintegration.

[0031] In the present invention, it is preferable that the partially pregelatinized starch used is contained within the granules from the viewpoint of solubility and disintegration properties.

[0032] The amount of partially pregelatinized starch used in the present invention is preferably 0.5 to 10% by mass, more preferably 1 to 7% by mass, and even more preferably 1 to 5% by mass, relative to the total mass of the orally disintegrating tablets of the present invention, from the viewpoint of balancing disintegration properties, storage stability, and moldability.

[0033] The amount of partially pregelatinized starch used in the present invention is preferably 1 to 10% by mass, more preferably 2.5 to 7% by mass, and even more preferably 4 to 6% by mass, based on the total mass of the granules of the present invention, from the viewpoint of balancing disintegration properties, storage stability, and moldability.

[0034] The orally disintegrating tablet of the present invention may further contain croscarmellose sodium.

[0035] The amount of croscarmellose sodium used in the present invention is preferably 1 to 10% by mass, and more preferably 2 to 8% by mass, relative to the total mass of the orally disintegrating tablets of the present invention, from the viewpoint of disintegration properties and other factors.

[0036] The orally disintegrating tablets of the present invention may further contain other additives.

[0037] The additives can be any pharmaceutically acceptable substances, such as excipients, binders, surfactants, lubricants, colorants, fluidizers, preservatives, sweeteners, flavoring agents, fragrances, and stabilizers. These may be used individually or in combination of two or more.

[0038] The orally disintegrating tablets of the present invention include uncoated tablets. In the present invention, an uncoated tablet refers to a tablet that is not coated with film or sugar.

[0039] The orally disintegrating tablets of the present invention may be made by applying a film coating or sugar coating to a plain tablet, resulting in film-coated tablets or sugar-coated tablets.

[0040] The hardness of the orally disintegrating tablets of the present invention is preferably 15N or more and 60N or less, and more preferably 20N or more and 50N or less.

[0041] [Manufacturing method for orally disintegrating tablets] Next, a method for producing the orally disintegrating tablets of the present invention will be described.

[0042] The present invention is characterized by using apixaban or a salt thereof or a solvate thereof and D-mannitol having a D90 of 200 to 400 μm. For example, it can be produced by a method including a tableting step of mixing granules containing (a) apixaban or a salt thereof or a solvate thereof and optionally other components ((b) one or more selected from the group consisting of D-mannitol and other additives) with an additive and compressing the resulting mixture into tablets.

[0043] The above granules can be obtained by a granulation process in which a composition containing component (a) and, if necessary, component (b) is granulated in accordance with a known granulation method described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia, etc.

[0044] Granulation in the granulation process may be carried out by either a wet granulation method or a dry granulation method. Specifically, examples include extrusion granulation, rolling granulation, agitation granulation, fluidized bed granulation, spray drying granulation, and crushing granulation. The granules obtained in the granulation process may be dried before being used in the tableting process. [Examples]

[0045] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0046] The measurement conditions for each measurement in this embodiment are as follows.

[0047] <Dissolution Test> The dissolution test was performed according to Method 2 of the Japanese Pharmacopoeia, with a paddle rotation speed of 50 rpm, and water (900 mL) was used as the test solution.

[0048] <Disintegration Test> Using the apparatus for the disintegration test method of the Japanese Pharmacopoeia, the amount of test solution in the beaker was set so that when the tester was at its highest point, the mesh surface of the tester was at least 15 mm below the liquid surface, and when the tester was at its lowest point, the mesh surface was at least 25 mm from the bottom of the beaker, so that the tester was not completely submerged. The temperature of the test solution was in the range of 37±2°C, the number of strokes was 30 back-and-forth movements per minute, and water was used as the test solution. The disintegration time of each sample was recorded in order from the fastest to the slowest. After 60 seconds, the tester was lifted out of the test solution and the disintegration of the samples was observed.

[0049] In addition, in this example, D-mannitol, partially pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, ferric oxide, yellow ferric oxide, crystalline cellulose, and magnesium stearate were used as follows. D-mannitol: Pearitol 200SD (Roquette) or Pearitol 100SD (Roquette), Partially pregelatinized starch: PCS PC-10 (Asahi Kasei), Croscarmellose sodium: Ac-Di-Sol (Dupont), Sodium lauryl sulfate: SLS (Nikko Chemicals), Iron oxide: Iron oxide (Kishi Kasei), Yellow iron oxide: Yellow iron oxide (Kishi Kasei), Crystalline cellulose: Ceolus UF-702 (Asahi Kasei), Magnesium stearate: Magnesium stearate-S (Taihei Chemical Industry)

[0050] (Example 1) An orally disintegrating tablet containing 5 mg of apixaban per tablet (weight 160 mg, hardness 40 N, round, diameter 8.0 mm, thickness 3.4 mm) was obtained by the following process.

[0051] (1) 25 g of apixaban (D90: 111 μm), 250 g of D-mannitol (PEARLITOL 200 SD, D50 = 150 μm, D90 = 240 μm), 15 g of croscarmellose sodium, 15 g of partially pregelatinized starch, and 0.2 g of ferric oxide were placed in a high-speed stirring granulator. Next, 10 g of sodium lauryl sulfate was dissolved in 100 mL of purified water, and this solution was sprayed into the high-speed stirring granulator using a sprayer to granulate (granulation process).

[0052] (2) The granules obtained in the above process were dried (drying process), and then sized using a JIS sieve (sizing process).

[0053] (3) Next, 355 g of D-mannitol, 25 g of croscarmellose sodium, 100 g of crystalline cellulose, 0.2 g of ferric oxide, and 5 g of magnesium stearate were added to the granules obtained in the granule sizing step described above and mixed, and then compressed into tablets (tabletization step) to obtain the orally disintegrating tablets of Example 1.

[0054] The orally disintegrating tablet of Example 1 had a dissolution rate of 74.4% (water) 15 minutes after the start of the dissolution test, and a disintegration time of 31 seconds. Furthermore, the orally disintegrating tablet of Example 1, when stored in a PTP sheet at 40°C and 75% RH for 3 months, had a disintegration time of 48 seconds, and when stored for 6 months, it had a disintegration time of 49 seconds, showing little change in disintegration time.

[0055] (Example 2) An orally disintegrating tablet containing 2.5 mg of apixaban per tablet (weight 80 mg, hardness 40 N, round, diameter 6.0 mm, thickness 2.9 mm) was obtained by the following process.

[0056] (1) 25 g of apixaban (D90: 111 μm), 250 g of D-mannitol (PEARLITOL 200 SD, D50 = 150 μm, D90 = 240 μm), 15 g of croscarmellose sodium, 15 g of partially pregelatinized starch, and 0.2 g of yellow ferric oxide were placed in a high-speed stirring granulator. Next, 10 g of sodium lauryl sulfate was dissolved in 100 mL of purified water, and this solution was sprayed into the high-speed stirring granulator using a sprayer to granulate (granulation process).

[0057] (2) The granules obtained in the above process were dried (drying process), and then sized using a JIS sieve (sizing process).

[0058] (3) Next, 355 g of D-mannitol, 25 g of croscarmellose sodium, 100 g of crystalline cellulose, 0.2 g of yellow ferric oxide, and 5 g of magnesium stearate were added to the granules obtained in the granule sizing step described above and mixed, and then compressed into tablets (tabletization step) to obtain the orally disintegrating tablets of Example 2. The orally disintegrating tablet of Example 2 had a dissolution rate of 76.9% (water) 15 minutes after the start of the dissolution test, and a disintegration time of 27 seconds. Furthermore, the orally disintegrating tablet of Example 2, when stored in a PTP sheet at 40°C and 75% RH for 3 months, had a disintegration time of 42 seconds, and when stored for 6 months, it had a disintegration time of 41 seconds, showing little change in disintegration time.

[0059] (Comparative Example 1) Comparative Example 1 was manufactured in the same manner as in Example 1, except that the amount of apixaban per tablet was as shown in Table 1.

[0060] [Table 1]

[0061] Comparative Example 1, which used D-mannitol (Pearitol 100SD, D50=100 μm, D90=185 μm) instead of D-mannitol (Pearitol 200SD) used in Examples 1 and 2, showed good initial dissolution and disintegration properties. However, after storage at 40°C and 75% RH for 3 months in a PTP sheet, the disintegration time was 87 seconds, and after storage for 6 months, the disintegration time was 392 seconds, indicating a significant change in disintegration time. [Industrial applicability]

[0062] The present invention provides an apixaban-containing orally disintegrating tablet that maintains its disintegration properties even after storage.

Claims

1. An orally disintegrating tablet characterized by containing (a) apixaban or a salt or solvate thereof, and (b) D-mannitol, wherein the D90 of (b) D-mannitol is 200 to 400 μm.

2. The orally disintegrating tablet according to claim 1, characterized in that it contains (a) apixaban or a salt or solvate thereof, and (b) D-mannitol inside the granules.

3. An orally disintegrating tablet according to claim 1 or 2, characterized in that it contains partially pregelatinized starch inside the granules.

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