JP2023050190A - Apixaban-containing orally disintegrating tablet and manufacturing method thereof - Google Patents

Abstract

To provide an apixaban-containing orally disintegrating tablet having required disintegration properties while maintaining the amorphous stability of apixaban, and to provide a method for producing an apixaban-containing orally disintegrating tablet having required disintegration properties while maintaining the amorphous stability of apixaban.SOLUTION: According to one embodiment of the invention, an apixaban-containing orally disintegrating tablet contains an apixaban solid dispersion in which amorphous apixaban is dispersed, using a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable acrylic polymer as a carrier.SELECTED DRAWING: None

Description

One embodiment of the present invention relates to an orally disintegrating tablet comprising an apixaban solid dispersion. Alternatively, one embodiment of the present invention relates to a method for producing an orally disintegrating tablet containing an apixaban solid dispersion.

Apixaban (1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c ]pyridine-3-carbboxamide) is an oral anticoagulant that reversibly inhibits blood coagulation activation factor X (FXa), and is effective in the treatment of thromboembolic diseases (Patent Document 1). Since apixaban is a poorly soluble drug, in Patent Document 1, a solid amorphous dispersion containing amorphous apixaban and a polymer selected from hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose is used. , which improves the solubility of apixaban. However, Patent Document 1 addresses the issue of controlling the release of apixaban from apixaban-containing preparations, does not describe the stability of amorphous apixaban, and does not discuss whether apixaban is maintained in an amorphous form in the preparation. has not been considered at all.

In addition, for the purpose of improving ease of administration, etc., it is desired to make an apixaban-containing preparation into an orally disintegrating tablet, which is a dosage form that is easy to swallow for elderly people, patients with swallowing difficulties, and the like. When an apixaban-containing preparation is used as an orally disintegrating tablet, excellent disintegration properties are required, but no results have been reported so far on the disintegration properties of an apixaban-containing orally disintegrating tablet.

Japanese Patent No. 5775071

From the description in Patent Document 1, apixaban is a poorly soluble drug, and the use of an apixaban solid dispersion is expected to improve the solubility of apixaban. On the other hand, as a result of investigation by the present inventors, it was found that apixaban has low stability in an amorphous form and is easily crystallized even in a solid dispersion. There is a need to improve the amorphous stability of apixaban in formulations.

Furthermore, in order to realize an orally disintegrating tablet containing apixaban, it is necessary to provide an orally disintegrating tablet containing apixaban that has excellent disintegrability while stably maintaining apixaban in an amorphous form in the formulation. .

The present invention is intended to solve the above problems, and to provide an apixaban-containing orally disintegrating tablet having the required disintegration properties while maintaining the amorphous stability of apixaban in the formulation. one of the purposes. Alternatively, in one embodiment, an object is to provide a method for producing an orally disintegrating tablet containing apixaban that has the required disintegration properties while maintaining the amorphous stability of apixaban in the formulation. .

According to one embodiment of the present invention, an orally disintegrating solid dispersion comprising apixaban solid dispersion in which amorphous apixaban is dispersed in a pharmaceutically acceptable cellulosic polymer or a pharmaceutically acceptable acrylic polymer as a carrier. A lock is provided.

The carrier may be 10% by weight or more and 100% by weight or less of hypromellose relative to the weight of amorphous apixaban contained in the apixaban solid dispersion.

Hydroxypropyl cellulose or aminoalkyl methacrylate copolymer E may be used as the carrier in an amount of more than 10% by weight and not more than 100% by weight based on the weight of the amorphous apixaban contained in the apixaban solid dispersion.

It may further comprise a disintegrant and one or more pharmaceutically acceptable excipients.

According to one embodiment of the present invention, apixaban and a pharmaceutically acceptable cellulosic polymer or a pharmaceutically acceptable acrylic polymer are dissolved in a solvent to prepare a solution, and by spray drying, the The solvent is removed to obtain an apixaban solid dispersion in which amorphous apixaban is dispersed using the pharmaceutically acceptable cellulose-based polymer or pharmaceutically acceptable acrylic polymer as a carrier. , a disintegrant, and one or more pharmaceutically acceptable excipients, are mixed and tableted.

A solution may be prepared so as to contain 10% by weight or more and 100% by weight or less of hypromellose as a carrier with respect to the weight of amorphous apixaban contained in the apixaban solid dispersion.

A solution containing more than 10% by weight and 100% by weight or less of hydroxypropyl cellulose or aminoalkyl methacrylate copolymer E as the carrier relative to the weight of the amorphous apixaban contained in the apixaban solid dispersion may be prepared.

According to one embodiment of the present invention, there is provided an orally disintegrating tablet containing apixaban with the required disintegration properties while maintaining the amorphous stability of apixaban. Alternatively, according to one embodiment of the present invention, there is provided a method for producing an apixaban-containing orally disintegrating tablet having the required disintegration properties while maintaining the amorphous stability of apixaban.

Hereinafter, the apixaban-containing orally disintegrating tablet and the method for producing the same according to the present invention will be described in detail. However, the apixaban-containing orally disintegrating tablet and the method for producing the same of the present invention should not be construed as being limited to the description of the embodiments and examples below.

As a result of studies by the present inventors, it was found that the polymer used as the carrier of the solid dispersion also has a function as a binder, so that the content of the polymer in the formulation leads to a delay in the disintegration time. Therefore, in order to provide an apixaban-containing orally disintegrating tablet with excellent disintegration properties, it is necessary to study the type and content of the polymer in the apixaban-containing orally disintegrating tablet.

The apixaban-containing orally disintegrating tablet according to the present invention contains an apixaban solid dispersion. In one embodiment, the apixaban solid dispersion comprises amorphous apixaban and a pharmaceutically acceptable cellulosic or pharmaceutically acceptable acrylic polymer as a carrier. In one embodiment, the apixaban solid dispersion is pharmaceutical composition particles in which amorphous apixaban is dispersed in a pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer as a carrier. .

In one embodiment, the apixaban solid dispersion according to the present invention is a pharmaceutical composition comprising amorphous apixaban and a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable acrylic polymer as a carrier. It is a particle of matter. In the apixaban solid dispersion according to the present embodiment, amorphous apixaban is dispersed in a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable acrylic polymer as a carrier, The amorphous state of apixaban can be maintained.

The pharmaceutically acceptable cellulose-based polymer contained as a carrier in the apixaban solid dispersion according to the present embodiment is particularly limited as long as it is a polymer capable of maintaining the amorphous state of apixaban in the apixaban solid dispersion. not. Cellulosic polymers can include, for example, one or more polymers selected from hydroxypropylcellulose, hypromellose, and hypromellose acetate succinate as carriers.

The pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion according to the present embodiment is particularly limited as long as it is a polymer capable of maintaining the amorphous state of apixaban in the apixaban solid dispersion. not. As the acrylic polymer, for example, one or more polymers selected from aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and ammonioalkyl methacrylate copolymer can be included as a carrier. .

In general, polymers such as polyethylene glycol, polyvinylpyrrolidone, methacrylic acid copolymers and cellulose derivatives, and low molecular weight molecules such as urea and sugar are also used as solid dispersion carriers. However, whether or not the amorphous state of apixaban can be maintained varies greatly depending on the type of polymer or low-molecular weight used as a carrier for the solid dispersion. Therefore, it is not easy to select a carrier that can maintain the amorphous state of apixaban. Furthermore, it is very difficult to optimize the carrier contained in the apixaban solid dispersion in order to obtain rapid disintegration of the orally disintegrating tablet.

In one embodiment, greater than 10% and less than or equal to 100% by weight of a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable An acrylic polymer is included as a carrier in the apixaban solid dispersion. In one embodiment, the pharmaceutically acceptable cellulose-based polymer or pharmaceutically acceptable acrylic polymer is 50% by weight or less relative to the weight of amorphous apixaban contained in the apixaban solid dispersion. may be included in the range. In one embodiment, the apixaban solid dispersion contains 10% by weight or more and 100% by weight or less of hypromellose as a carrier relative to the weight of amorphous apixaban contained in the apixaban solid dispersion.

If the pharmaceutically acceptable cellulose-based polymer or pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion is less than 10% by weight with respect to amorphous apixaban, amorphous apixaban Difficult to maintain quality. In addition, even if the pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion exceeds 100% by weight relative to the weight of amorphous apixaban, The amorphous state of apixaban is maintained.

On the other hand, in an orally disintegrating tablet that requires rapid disintegration, a high content of a polymer that also functions as a binder leads to a delay in disintegration time. Therefore, when the pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion exceeds 100% by weight relative to the weight of amorphous apixaban, apixaban Rapid disintegration cannot be obtained when the solid dispersion is used for an orally disintegrating tablet.

[orally disintegrating tablet]
The apixaban-containing orally disintegrating tablet according to the present invention further comprises a disintegrant and one or more pharmaceutically acceptable additives in addition to the apixaban solid dispersion described above. The apixaban-containing orally disintegrating tablet contains 2.5 mg or 5 mg of amorphous apixaban per tablet, but is not limited thereto, and the formulation can be changed as necessary.

Pharmaceutically acceptable additives contained in the apixaban-containing orally disintegrating tablet include excipients, binders, disintegrants, stabilizers, corrigents, lubricants and flavoring agents. One or more of these additives can be selected to constitute an orally disintegrating tablet containing apixaban, but it is preferable to include an excipient and a disintegrant in order to impart properties that disintegrate in the oral cavity. . It may also contain pre-mixed additives in combination of two or more of these additives.

Excipients can be selected from, for example, sugars, sugar alcohols, starches, celluloses, carmelloses, gum arabic, dextran, pullulan, silicates, phosphates, carbonates and sulfates. Sugars include, for example, lactose, sucrose, glucose, trehalose, maltose and the like. Sugar alcohols include mannitol, erythritol, xylitol, sorbitol, isomalt and the like. Starches include corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, dextrin and the like. Examples of celluloses include crystalline cellulose and low-substituted hydroxypropyl cellulose. Carmelloses include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium and the like. Examples of silicates include light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminometasilicate. Phosphates include calcium hydrogen phosphate and the like. Carbonates include calcium carbonate, magnesium carbonate, and the like. Calcium sulfate etc. are mentioned as a sulfate. These excipients can be used singly or in combination of two or more.

Binders include, for example, celluloses such as crystalline cellulose, hydroxypropyl cellulose, hypromellose, hydroxyethylmethyl cellulose, ethyl cellulose and methyl cellulose, povidone, polyvinyl acetal diethylaminoacetate, fully saponified polyvinyl alcohol, partially saponified polyvinyl alcohol, carboxyvinyl polymer, vinyl polymer substances such as polyvinyl chloride, aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), acrylic polymer substances such as ethyl acrylate/methyl methacrylate copolymer dispersions, It can be selected from stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogol, starch and the like.

Disintegrants can be selected from, for example, carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, celluloses such as croscarmellose sodium and methylcellulose, starches such as partially pregelatinized starch and corn starch, crospovidone, and the like. can.

Stabilizers are, for example, ascorbic acid, sodium ascorbate, aspartic acid, sodium aspartate, arginine, sodium edetate, anhydrous citric acid, citric acid hydrate, sodium citrate hydrate, sodium hydroxide, hydroxide It can be selected from magnesium, stearic acid, potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, magnesium carbonate and the like.

The flavoring agent can be selected from, for example, ascorbic acid, aspartic acid, sodium aspartate, aspartame, caramel, hydrogenated maltose starch syrup, glycyrrhizic acid, saccharin, sodium saccharin, sucralose, purified stevia extract, refined white sugar, menthol, and the like. .

Lubricants can be selected from, for example, hydrous silicon dioxide, light anhydrous silicic acid, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, talc, leucine, and the like.

In the apixaban-containing orally disintegrating tablet according to the present embodiment, the pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer that constitutes the apixaban solid dispersion maintains the amorphous state of apixaban. be able to. When the pharmaceutically acceptable cellulose-based polymer or pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion is less than 10% by weight with respect to the weight of amorphous apixaban, It is difficult to maintain the amorphous state. In addition, even if the pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion exceeds 100% by weight relative to the weight of amorphous apixaban, The amorphous state of apixaban is maintained.

On the other hand, in an orally disintegrating tablet that requires rapid disintegration, a high content of a polymer that also functions as a binder leads to a delay in disintegration time. Therefore, when the pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer contained as a carrier in the apixaban solid dispersion exceeds 100% by weight relative to the weight of amorphous apixaban, apixaban Rapid disintegration cannot be obtained when the solid dispersion is used for an orally disintegrating tablet.

[Method for producing apixaban solid dispersion]
The apixaban solid dispersion according to this embodiment is a spray-dried product produced by a spray-drying method. For example, apixaban and the above-described pharmaceutically acceptable cellulose polymer or pharmaceutically acceptable acrylic polymer are dissolved in a solvent to prepare a solution. In the present embodiment, the apixaban used as a raw material for producing the apixaban solid dispersion may be amorphous apixaban or apixaban crystals as long as the apixaban solid dispersion is maintained amorphous. may As a solvent, a solvent capable of dissolving apixaban and a pharmaceutically acceptable cellulose polymer or a pharmaceutically acceptable acrylic polymer can be selected from pharmaceutically acceptable solvents. Since apixaban is a poorly soluble drug, for example, a mixed solvent of dichloromethane and ethanol (mixture ratio 4:1) can be used.

In one embodiment, 10% by weight or more and 100% by weight or less of a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable acrylic based on the weight of amorphous apixaban contained in the apixaban solid dispersion A solution is prepared to contain the system polymer as a carrier.

Solvent is removed from the solution by spray drying using a spray dryer. Thereby, particles containing amorphous apixaban and a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable acrylic polymer as a carrier can be obtained.

[Method for producing apixaban-containing orally disintegrating tablet]
The apixaban-containing orally disintegrating tablet according to this embodiment is obtained by mixing the apixaban solid dispersion, the disintegrant, and one or more of the above-described pharmaceutically acceptable additives, and tableting the resulting mixture. It can be manufactured by Moreover, you may use the additive which combined and mixed 2 or more types of additives in advance.

In this embodiment, apixaban can be maintained in an amorphous state by producing the apixaban solid dispersion by a spray drying method. In addition, a pharmaceutically acceptable cellulose-based polymer or a pharmaceutically acceptable acrylic polymer in an amount of 10% by weight or more and 100% by weight or less based on the weight of amorphous apixaban contained in the apixaban solid dispersion. By including it in the apixaban solid dispersion as a carrier, in the apixaban-containing orally disintegrating tablet, the amorphous state of apixaban can be maintained and rapid disintegration can be obtained.

[Amorphous evaluation]
The amorphous state of apixaban can be evaluated by powder X-ray diffractometry. As used herein, the term "amorphous" means that peaks derived from crystalline components are not detected in a diffraction pattern obtained by powder X-ray diffraction measurement. "No peak detected" means that a broad halo pattern is observed with respect to the baseline in the diffraction pattern, and no significant peak derived from a crystalline component is observed.

[Evaluation of disintegration]
In the present specification, the disintegration property of an orally disintegrating tablet containing apixaban is evaluated by measuring the disintegration time in a sensory test by two subjects, and taking the average value as the disintegration time of each orally disintegrating tablet. do.

[Study of carrier for solid dispersion]
A carrier for apixaban solid dispersion was investigated.

[Example 1]
Hydroxypropyl cellulose was used as a carrier. 15 g of apixaban crystals and 15 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda Co., Ltd.) were dissolved in 530 g of a dichloromethane/ethanol mixture (mixture ratio: 4:1). The resulting solution was spray-dried with a spray dryer (Mini Spray Dryer B-290, BUCHI) and the solvent was removed to obtain particles of the apixaban solid dispersion of Example 1.

[Example 2]
Apixaban solid dispersion of Example 2 was obtained by the same production method as in Example 1, except that the carrier was changed to hypromellose (TC-5 (registered trademark) E, Shin-Etsu Chemical Co., Ltd.).

[Example 3]
Apixaban solid dispersion of Example 3 was obtained by the same production method as in Example 1, except that the carrier was changed to aminoalkyl methacrylate copolymer E (EUDRAGIT (registered trademark) EPO, Evonik Roehm).

[Comparative Example 1]
Apixaban solid dispersion of Comparative Example 1 was obtained by the same production method as in Example 1, except that the carrier was changed to polyvinylpyrrolidone (K-30, Daiichi Kogyo Seiyaku Co., Ltd.).

[Reference example 1]
Hydroxypropyl cellulose was used as the polymer. A mixture of Reference Example 1 was obtained by mixing 1 g of amorphous apixaban and 1 g of hydroxypropylcellulose (HPC-SSL, Nippon Soda Co., Ltd.) in a plastic bag.

[Reference example 2]
A mixture of Reference Example 2 was obtained by the same production method as in Reference Example 1, except that the polymer was changed to hypromellose (TC-5 (registered trademark) E, Shin-Etsu Chemical Co., Ltd.).

[Reference example 3]
A mixture of Reference Example 3 was obtained by the same manufacturing method as in Reference Example 1, except that the polymer was changed to aminoalkyl methacrylate copolymer E (EUDRAGIT (registered trademark) EPO, Evonik Roehm).

[Amorphous evaluation]
It was confirmed by powder X-ray diffraction measurement that the apixaban solid dispersions of Examples 1 to 3 and Comparative Example 1 and the mixtures of Reference Examples 1 to 3 were in an amorphous state. Each sample was stored under open conditions of 25° C. and 75% relative humidity for one month, and the amorphous state was confirmed by powder X-ray diffraction measurement. For measurement, powder X-ray diffractometer Bruker D8 ADVANCE is used, Cu-Ka ray, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0 °, scan speed: 1 sec / step, step Size: Measured under the condition of 0.015°.

Table 1 shows the evaluation results of the amorphous state.

From the results in Table 1, it was shown that the apixaban solid dispersions of Examples 1 to 3 using a cellulose polymer or acrylic polymer as a carrier maintained an amorphous state of apixaban even after storage for one month. . On the other hand, in the apixaban solid dispersion of Comparative Example 1 using polyvinylpyrrolidone as a carrier, it was found that apixaban could not maintain an amorphous state after storage for one month. Further, from the results of Reference Examples 1 to 3, it was clarified that the amorphous state of apixaban cannot be maintained only by containing a cellulose polymer or an acrylic polymer, and it is necessary to prepare a solid dispersion. rice field.

Using the apixaban solid dispersions of Examples 1 to 3 and Comparative Example 1 above, orally disintegrating tablets were produced.

[Example 4]
Apixaban solid dispersion of Example 1 5 g, sodium lauryl sulfate (Emal OS, Kao Corporation) 1 g, D-mannitol (Granutol F, Freund Corporation) 7.5 g, D-mannitol (Mannitol-P, Mitsubishi Shoji Life Science Co., Ltd.) 69.255 g, crystalline cellulose (CEOLUS (registered trademark) PH-101, Asahi Kasei Corporation) 8.55 g, low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) NBD-022, Shin-Etsu Chemical Industry Co., Ltd.) 4.275 g, crospovidone (Kollidon (registered trademark) CL-F, BASF Japan) 1.71 g, crospovidone (Kollidon (registered trademark) CL-M, BASF Japan) 1.71 g, and magnesium stearate (Vegetable, Taihei Kagaku Sangyo Co., Ltd.) 1 g was mixed in a plastic bag and compressed with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain 100 mg of apixaban-containing orally disintegrating tablet of Example 4. rice field.

[Example 5]
An apixaban-containing orally disintegrating tablet of Example 5 was obtained by the same manufacturing method as in Example 4, except that the apixaban solid dispersion of Example 2 was used.

[Example 6]
An apixaban-containing orally disintegrating tablet of Example 6 was obtained by the same manufacturing method as in Example 4, except that the apixaban solid dispersion of Example 3 was used.

[Comparative Example 2]
An apixaban-containing orally disintegrating tablet of Comparative Example 2 was obtained by the same manufacturing method as in Example 4, except that the apixaban solid dispersion of Comparative Example 1 was used.

[Amorphous evaluation]
It was confirmed by powder X-ray diffractometry that the apixaban-containing orally disintegrating tablets of Examples 4 to 6 and Comparative Example 2 were in an amorphous state. Each sample was stored under open conditions of 25° C. and 75% relative humidity for one month, and the amorphous state was confirmed by powder X-ray diffraction measurement. For measurement, powder X-ray diffractometer Bruker D8 ADVANCE is used, Cu-Ka ray, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0 °, scan speed: 1 sec / step, step Size: Measured under the condition of 0.015°.

[Evaluation of disintegrating property of orally disintegrating tablet]
The apixaban-containing orally disintegrating tablets of Examples 4 to 6 were evaluated for disintegration. For disintegration, the disintegration time was measured by a sensory test by two subjects, and the average value was taken as the disintegration time of each orally disintegrating tablet. For the orally disintegrating tablet of Comparative Example 2, apixaban crystallized after storage for one month, so the orally disintegrating time was not measured.

Table 2 shows the evaluation results of the amorphous state and the evaluation results of the disintegrating properties of the orally disintegrating tablet.

From the results in Table 2, the apixaban-containing orally disintegrating tablets of Examples 4 to 6 containing the apixaban solid dispersion with a cellulose polymer or acrylic polymer as a carrier capable of maintaining an amorphous state in a solid dispersion state. showed that apixaban remained amorphous even after 1 month of storage. On the other hand, the apixaban-containing orally disintegrating tablet of Comparative Example 2, which contains the apixaban solid dispersion using polyvinylpyrrolidone as a carrier, which cannot maintain an amorphous state in the state of solid dispersion, showed that apixaban did not disintegrate after storage for one month. It became clear that the amorphous state could not be maintained.

In addition, from the results in Table 2, the apixaban-containing oral cavity of Examples 4 to 6 containing the apixaban solid dispersion using a cellulose-based polymer or acrylic polymer as a carrier capable of maintaining an amorphous state in a solid dispersion state It was found that the disintegrating tablet exhibits rapid disintegration within 60 seconds.

[Examination of carrier content of solid dispersion]
In the apixaban solid dispersions of Examples 1 to 3, 100% by weight of carrier was added to the weight of amorphous apixaban. The effect of carrier content on maintaining amorphousness was investigated.

[Example 7]
In Example 7, the content of the carrier was adjusted to 50% by weight with respect to the weight of amorphous apixaban. Hydroxypropyl cellulose was used as a carrier. 20 g of apixaban crystals and 10 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda Co., Ltd.) were dissolved in 705 g of a dichloromethane/ethanol mixture (mixture ratio: 4:1). The resulting solution was spray-dried with a spray dryer (Mini Spray Dryer B-290, BUCHI) and the solvent was removed to obtain particles of the apixaban solid dispersion of Example 7.

[Example 8]
Apixaban solid dispersion of Example 8 was obtained by the same production method as in Example 7, except that the carrier was changed to hypromellose (TC-5 (registered trademark) E, Shin-Etsu Chemical Co., Ltd.).

[Example 9]
Apixaban solid dispersion of Example 9 was obtained by the same production method as in Example 7, except that the carrier was changed to aminoalkyl methacrylate copolymer E (EUDRAGIT (registered trademark) EPO, Evonik Roehm).

[Comparative Example 3]
In Comparative Example 3, the content of the carrier was adjusted to 10% by weight with respect to the weight of amorphous apixaban. Hydroxypropyl cellulose was used as a carrier. 22 g of apixaban crystals and 2.2 g of hydroxypropyl cellulose (HPC-SSL, Nippon Soda Co., Ltd.) were dissolved in 774.2 g of a dichloromethane/ethanol mixture (mixture ratio: 4:1). The resulting solution was spray-dried with a spray dryer (Mini Spray Dryer B-290, BUCHI) and the solvent was removed to obtain particles of apixaban solid dispersion of Comparative Example 3.

[Example 10]
Apixaban solid dispersion of Example 10 was obtained by the same production method as in Comparative Example 3, except that the carrier was changed to hypromellose (TC-5 (registered trademark) E, Shin-Etsu Chemical Co., Ltd.).

[Comparative Example 4]
Apixaban solid dispersion of Comparative Example 4 was obtained by the same production method as in Comparative Example 3, except that the carrier was changed to aminoalkyl methacrylate copolymer E (EUDRAGIT (registered trademark) EPO, Evonik Roehm).

[Amorphous evaluation]
It was confirmed by powder X-ray diffraction measurement that the apixaban solid dispersions of Examples 7-10 and Comparative Examples 3-4 were in an amorphous state. Each sample was stored under open conditions of 25° C. and 75% relative humidity for one month, and the amorphous state was confirmed by powder X-ray diffraction measurement. For measurement, powder X-ray diffractometer Bruker D8 ADVANCE is used, Cu-Ka ray, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0 °, scan speed: 1 sec / step, step Size: Measured under the condition of 0.015°.

Table 3 shows the evaluation results of the amorphous state.

From the results in Table 3, the apixaban solid dispersions of Examples 7 to 9 containing 50% by weight of the cellulose-based polymer or acrylic polymer as a carrier with respect to amorphous apixaban retained apixaban even after storage for one month. It was shown to remain amorphous. In addition, it was shown that the apixaban solid dispersion of Example 10, which contains 10% by weight of hypromellose as a carrier relative to amorphous apixaban, maintains the amorphous state of apixaban even after storage for one month. . On the other hand, even the apixaban solid dispersion containing 10% by weight of the cellulose-based polymer or acrylic polymer as a carrier relative to the amorphous apixaban contained Comparative Example 3 containing hydroxypropyl cellulose and aminoalkyl methacrylate copolymer E. It was found that the apixaban solid dispersion of Comparative Example 4 could not maintain the amorphous state of apixaban after storage for one month.

Using the apixaban solid dispersions of Examples 7-10 and Comparative Examples 3-4 above, orally disintegrating tablets were produced.

[Example 11]
Apixaban solid dispersion of Example 7 1.88 g, sodium lauryl sulfate (Emar OS, Kao Corporation) 0.5 g, D-mannitol (Granutol F, Freund Corporation) 4.375 g, D-mannitol (mannitol -P, Mitsubishi Corporation Life Sciences Co., Ltd.) 34.6275 g, crystalline cellulose (CEOLUS (registered trademark) PH-101, Asahi Kasei Corporation) 4.275 g, low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) NBD- 022, Shin-Etsu Chemical Co., Ltd.) 2.1375 g, crospovidone (Kollidon (registered trademark) CL-F, BASF Japan) 0.855 g, crospovidone (Kollidon (registered trademark) CL-M, BASF Japan) 0.855 g, and 0.5 g of magnesium stearate (vegetable, Taihei Kagaku Sangyo Co., Ltd.) were mixed in a plastic bag and tableted with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.), containing 100 mg of apixaban of Example 11. An orally disintegrating tablet was obtained.

[Example 12]
An apixaban-containing orally disintegrating tablet of Example 12 was obtained by the same production method as in Example 11, except that the apixaban solid dispersion of Example 8 was used.

[Example 13]
An apixaban-containing orally disintegrating tablet of Example 13 was obtained by the same manufacturing method as in Example 11, except that the apixaban solid dispersion of Example 9 was used.

[Comparative Example 5]
Apixaban solid dispersion of Comparative Example 3 1.38 g, sodium lauryl sulfate (Emar OS, Kao Corporation) 0.5 g, D-mannitol (Granutol F, Freund Corporation) 4.875 g, D-mannitol (mannite -P, Mitsubishi Corporation Life Sciences Co., Ltd.) 34.6275 g, crystalline cellulose (CEOLUS (registered trademark) PH-101, Asahi Kasei Corporation) 4.275 g, low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) NBD- 022, Shin-Etsu Chemical Co., Ltd.) 2.1375 g, crospovidone (Kollidon (registered trademark) CL-F, BASF Japan) 0.855 g, crospovidone (Kollidon (registered trademark) CL-M, BASF Japan) 0.855 g, and 0.5 g of magnesium stearate (vegetable, Taihei Kagaku Sangyo Co., Ltd.) were mixed in a plastic bag and tableted with a rotary tableting machine (Kikusui Seisakusho Co., Ltd.), containing 100 mg of apixaban of Comparative Example 5. An orally disintegrating tablet was obtained.

[Example 14]
An apixaban-containing orally disintegrating tablet of Example 14 was obtained by the same manufacturing method as in Comparative Example 5, except that the apixaban solid dispersion of Example 10 was used.

[Comparative Example 6]
An apixaban-containing orally disintegrating tablet of Comparative Example 6 was obtained by the same manufacturing method as in Comparative Example 5, except that the apixaban solid dispersion of Comparative Example 4 was used.

[Amorphous evaluation]
It was confirmed by powder X-ray diffraction measurement that the apixaban-containing orally disintegrating tablets of Examples 11 to 14 and Comparative Examples 5 and 6 were in an amorphous state. Each sample was stored under open conditions of 25° C. and 75% relative humidity for one month, and the amorphous state was confirmed by powder X-ray diffraction measurement. For measurement, powder X-ray diffractometer Bruker D8 ADVANCE is used, Cu-Ka ray, tube voltage 40 kV, tube current 40 mA, measurement range: 2θ = 10.0 to 25.0 °, scan speed: 1 sec / step, step Size: Measured under the condition of 0.015°.

[Evaluation of disintegrating property of orally disintegrating tablet]
The apixaban-containing orally disintegrating tablets of Examples 11 to 14 were evaluated for disintegration. The evaluation method is as described above. For the orally disintegrating tablets of Comparative Examples 5 and 6, the apixaban crystallized after storage for one month, so the orally disintegrating time was not measured.

Table 4 shows the evaluation results of the amorphous state and the evaluation results of the disintegrating properties of the orally disintegrating tablet.

From the results in Table 4, the apixaban-containing orally disintegrating tablets of Examples 11 to 13 using the apixaban solid dispersion containing 50% by weight of the cellulose-based polymer or acrylic polymer as a carrier relative to the weight of the amorphous apixaban. showed that apixaban remained amorphous even after 1 month of storage. In addition, the apixaban-containing orally disintegrating tablet of Example 14 using the apixaban solid dispersion containing 10% by weight of hypromellose as a carrier with respect to amorphous apixaban had amorphous apixaban even after storage for one month. shown to maintain the condition. On the other hand, even an apixaban-containing orally disintegrating tablet using an apixaban solid dispersion containing 10% by weight of apixaban as a carrier based on the weight of amorphous apixaban, a cellulose polymer or an acrylic polymer, still contains hydroxypropylcellulose. It was found that the apixaban-containing orally disintegrating tablets of Comparative Example 5 and Comparative Example 6 containing aminoalkyl methacrylate copolymer E were unable to maintain the amorphous state of apixaban after storage for one month.

In addition, from the results in Table 4, the apixaban-containing oral cavity of Examples 11 to 14 containing the apixaban solid dispersion using a cellulose polymer or an acrylic polymer as a carrier capable of maintaining an amorphous state in a solid dispersion state It was found that the disintegrating tablet exhibits rapid disintegration within 60 seconds. In comparison with Table 2, in the apixaban-containing orally disintegrating tablet using hydroxypropyl cellulose and hypromellose, when the content exceeds 100% by weight with respect to the weight of amorphous apixaban, the disintegration time becomes long and the disintegration time is rapid. It is clear that it does not show disintegrating properties.

Claims (7)

An apixaban-containing orally disintegrating tablet containing an apixaban solid dispersion in which amorphous apixaban is dispersed in a carrier of a pharmaceutically acceptable cellulose polymer or a pharmaceutically acceptable acrylic polymer. 2. The apixaban-containing orally disintegrating tablet according to claim 1, wherein the carrier is 10% by weight or more and 100% by weight or less of hypromellose relative to the weight of the amorphous apixaban contained in the apixaban solid dispersion. 2. The carrier according to claim 1, wherein more than 10% by weight and 100% by weight or less of hydroxypropyl cellulose or aminoalkyl methacrylate copolymer E is used as the carrier, based on the weight of the amorphous apixaban contained in the apixaban solid dispersion. Apixaban-containing orally disintegrating tablet as described. 4. The apixaban-containing orally disintegrating tablet according to any one of claims 1 to 3, further comprising a disintegrant and one or more pharmaceutically acceptable additives. dissolving apixaban and a pharmaceutically acceptable cellulose polymer or a pharmaceutically acceptable acrylic polymer in a solvent to prepare a solution;
Apixaban solid dispersion in which amorphous apixaban is dispersed in the pharmaceutically acceptable cellulose-based polymer or the pharmaceutically acceptable acrylic polymer as a carrier by removing the solvent from the solution by spray drying get a body
A method for producing an orally disintegrating tablet containing apixaban, wherein the apixaban solid dispersion, a disintegrant, and one or more pharmaceutically acceptable additives are mixed and tableted. 6. The solution according to claim 5, wherein the solution is prepared so as to contain 10% by weight or more and 100% by weight or less of hypromellose as the carrier with respect to the weight of the amorphous apixaban contained in the apixaban solid dispersion. Method for producing an apixaban-containing orally disintegrating tablet. The solution containing more than 10% by weight and 100% by weight or less of hydroxypropyl cellulose or aminoalkyl methacrylate copolymer E as the carrier relative to the weight of the amorphous apixaban contained in the apixaban solid dispersion The method for producing the apixaban-containing orally disintegrating tablet according to claim 5, wherein