JP2023008994A - Method for improving leachability of apixaban - Google Patents

Abstract

To provide a method for efficiently improving the leachability of apixaban from a pharmaceutical composition containing apixaban as a medicinal component, a pharmaceutical composition having improved leachability of apixaban, and a method for producing the pharmaceutical composition.SOLUTION: The present invention provides a method for improving the leachability of apixaban from a pharmaceutical composition containing apixaban as a medicinal component, the method including the step of changing the apixaban to amorphous using one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropyl cellulose, and a sugar alcohol.SELECTED DRAWING: None

Description

The present invention relates to a method for improving the dissolution of apixaban from a pharmaceutical composition containing apixaban as a medicinal ingredient, a pharmaceutical composition with improved dissolution of apixaban, and a method for producing the pharmaceutical composition.

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) inhibits factor Xa, the convergence point of the extrinsic and intrinsic blood coagulation pathways, thereby suppressing its downstream conversion of prothrombin to thrombin; It is a drug that exhibits a direct anticoagulant effect and an indirect antiplatelet effect (Non-Patent Document 1).

Since apixaban is almost insoluble in water (Non-Patent Document 1), various techniques have been developed to control its dissolution. For example, US Pat. No. 6,200,000 discloses a dosage form comprising a solubility-improved form of apixaban for controlling the release of apixaban. In addition, US Pat. No. 6,200,000 discloses a composition containing amorphous apixaban that is efficient, more economical, less hazardous, and environmentally friendly. Patent Document 3 describes the relationship between the particle size of apixaban and the dissolution properties of formulations, and Patent Document 4 describes a pharmaceutical composition with improved dissolution properties by containing granules containing apixaban and hydroxyethyl cellulose. is disclosed.

Japanese Patent Publication No. 2012-530141 International Publication No. 2013/164839 pamphlet International Publication No. 2017/182908 pamphlet International Publication No. 2020/127819 pamphlet

"Eliquis (registered trademark) tablets 2.5 mg Eliquis (registered trademark) tablets 5 mg" package insert

As described above, various formulations containing apixaban as a medicinal ingredient have been developed with the goal of improving dissolution. However, although there are inventions for controlling the particle size of the drug substance of apixaban for the sake of dissolution, for example, control of the particle size of the drug substance, especially excessive micronization, may require a great deal of energy. Overall manufacturing efficiency may be reduced.
Accordingly, the present invention provides a method for efficiently improving the dissolution of apixaban from a pharmaceutical composition containing apixaban as a medicinal ingredient, a pharmaceutical composition with improved dissolution of apixaban, and a method for producing the pharmaceutical composition. intended to provide

The present inventors have made intensive studies in order to solve the above problems. As a result, the present inventors have found that the dissolution of apixaban, which is a medicinal ingredient, is remarkably improved by amorphizing apixaban using a specific crystallization inhibitor, and completed the present invention.
The present invention is shown below.

[1] A method for improving the dissolution of apixaban from a pharmaceutical composition containing apixaban as a medicinal ingredient, comprising:
A method comprising amorphizing said apixaban with one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohols.
[2] The method according to [1] above, wherein the mixture of the apixaban and the crystallization inhibitor is heated to melt and then cooled to amorphize the apixaban.
[3] The method according to [1] or [2] above, wherein the pharmaceutical composition is a tablet.
[4] The method according to [3], further comprising the step of mixing the amorphous apixaban, the rapidly disintegrating granules, and the lubricant-containing mixture, followed by tableting.
[5] The method according to any one of [1] to [4], wherein polyvinylpyrrolidone is used as the crystallization inhibitor.
[6] The method according to [5] above, wherein a sugar alcohol is used in addition to polyvinylpyrrolidone as the crystallization inhibitor.
[7] The method according to any one of [1] to [4], wherein hydroxypropylcellulose is used as the crystallization inhibitor.
[8] containing the medicinal ingredients apixaban and a crystallization inhibitor,
The apixaban is amorphous, and
A pharmaceutical composition, wherein the crystallization inhibitor is one or more selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohol.
[9] A method for producing a pharmaceutical composition containing apixaban as a medicinal ingredient, comprising:
A method comprising amorphizing said apixaban with one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohols.

Since the apixaban-containing pharmaceutical composition according to the present invention is excellent in dissolution of the active ingredient apixaban, it enables effective absorption of apixaban from the gastrointestinal tract. Therefore, the apixaban-containing pharmaceutical composition according to the present invention is industrially very excellent as one form of preparations containing apixaban as a medicinal ingredient.

FIG. 1 is the X-ray structural diffraction data of apixaban drug substance and apixaban apixaban amorphized using a specific crystallization inhibitor. FIG. 2 is a graph showing the dissolution properties of tablets containing apixaban crystals or apixaban that has been made amorphous using a crystallization inhibitor into the first fluid (pH 1.2) for the dissolution test. FIG. 3 is a graph showing the dissolution properties of tablets containing apixaban crystals or apixaban made amorphous using a crystallization inhibitor into the second liquid (pH 6.8) of the dissolution test. FIG. 4 is a graph showing the dissolution from the tablet containing the coated amorphous apixaban solid dispersion powder to the first fluid (pH 1.2) for the dissolution test.

The method for improving the dissolution of apixaban from a pharmaceutical composition containing apixaban as a medicinal ingredient according to the present invention, and the method for producing a pharmaceutical composition containing apixaban as a medicinal ingredient according to the present invention are polyvinylpyrrolidone, hydroxypropyl Apixaban is amorphized using one or more crystallization inhibitors selected from cellulose and sugar alcohols.

The pharmaceutical composition according to the present invention contains apixaban as an active ingredient. The chemical name of apixaban is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo [ A 3,4-c]pyridine-3-carboxamide, apixaban has the following chemical structure and inhibits factor Xa, the convergence point of the extrinsic and intrinsic blood coagulation pathways, thereby inhibiting its downstream It inhibits the conversion of prothrombin to thrombin and exhibits direct anticoagulant and indirect antiplatelet effects.

Apixaban as a drug substance may be in the free form or in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of apixaban include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate; acetate, propionate, succinate; , glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, pamoate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate , salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, organic acid salts such as isethionate, and the like. .

Apixaban, which is the drug substance, is generally crystalline, but in the present invention, it is amorphized by a crystallization inhibitor, so the size is not particularly limited and may be adjusted as appropriate. For example, the volume-based cumulative 50% particle diameter (D ₅₀ ) can be 1 μm or more and 300 μm or less, preferably 10 μm or more and 100 μm or less. In addition, the volume-based cumulative 90% particle diameter (D ₉₀ ) can be 50 μm or more and 500 μm or less, preferably 90 μm or more, more preferably 100 μm or more, even more preferably 150 μm or more, and 400 μm or less. It is preferably 300 μm or less, more preferably 200 μm or less. In the present invention, a relatively large drug substance apixaban can be used, so the productivity of the pharmaceutical composition is high. In the present disclosure, the volume-based cumulative 50% particle diameter (D ₅₀ ) and the volume-based cumulative 90% particle diameter (D ₉₀ ) are measured on a volume basis using a laser diffraction particle size distribution analyzer.

The amount and ratio of apixaban in the pharmaceutical composition according to the present invention may be appropriately adjusted within a range in which apixaban can exhibit its effects. For example, the amount of apixaban per formulation such as one tablet can be 1 mg or more and 100 mg or less, preferably 2 mg or more, more preferably 5 mg or more, and preferably 50 mg or less, more preferably 20 mg or less. Even more preferably 15 mg or less or 10 mg or less. In addition, the ratio of apixaban per formulation can be 0.5% by mass or more and 20% by mass or less, preferably 1% by mass or more, more preferably 2% by mass or more, and 15% by mass or less. Preferably, it is 10% by mass or less, and even more preferably 5% by mass or less. For example, the amount of apixaban per tablet can be 2.5±0.25 mg or 5±0.5 mg.

In the present invention, apixaban is amorphized using one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohols. For example, the drug substance apixaban, which is generally crystalline, may be solidified in an amorphous state by a crystallization inhibitor after being melted or dissolved.

A crystallization inhibitor has a relatively low melting point and inhibits recrystallization of molten or dissolved apixaban. Specifically, it dissolves apixaban in a molten state and inhibits crystallization in the solidification process of apixaban. The crystallization inhibitors may be used singly or in combination of two or more.

Among the crystallization inhibitors, polyvinylpyrrolidone is a water-soluble polymer compound obtained by polymerizing N-vinyl-2-pyrrolidone. Although the molecular weight of polyvinylpyrrolidone used as a crystallization inhibitor is not particularly limited, for example, polyvinylpyrrolidone having a weight average molecular weight of 5,000 or more and 3,000,000 or less can be used. The K value (viscosity characteristic value) of polyvinylpyrrolidone is also not particularly limited, but, for example, one of 10 or more and 120 or less can be used.

Hydroxypropyl cellulose is a cellulose derivative in which some or all of the hydroxyl groups of cellulose are substituted with 2-hydroxypropyl groups.

A sugar alcohol is a kind of sugar produced by reduction of a carbonyl group of an aldose or a ketose. Examples of sugar alcohols include monosaccharide alcohols such as glycerin, erythritol, xylitol, mannitol and sorbitol; Mannitol, 4-O-α-D-glucopyranosyl-D-glucitol (maltitol), 6-O-α-D-glucopyranosyl-D-glucitol (isomaltitol), 4-O-β-D-galactopyrano Disaccharide alcohols such as cyl-D-glucitol (lactitol) are included. Isomalt is a mixture of 6-O-α-D-glucopyranosyl-D-sorbitol and 6-O-α-D-glucopyranosyl-D-mannitol.

Apixaban drug substance is amorphized, for example, by mixing the drug substance apixaban crystals with a crystallization inhibitor, heating until at least the apixaban crystals are melted or dissolved, and then cooling until solidification. do it. Means for melting or dissolving the mixture of the apixaban crystals and the crystallization inhibitor include, for example, a hot melt granulator and an extruder. The heating temperature may be appropriately adjusted within a range in which at least the apixaban crystals are melted or dissolved. The cooling conditions may be appropriately adjusted within a range in which apixaban is amorphized, but since a crystallization inhibitor is used, there is no particular need to increase the cooling rate, and cooling to room temperature is sufficient.

Alternatively, after dissolving the apixaban drug substance and the crystallization inhibitor in a solvent, the solvent may be distilled off. The solvent is not particularly limited as long as it can appropriately dissolve the apixaban drug substance and the crystallization inhibitor. Examples include alcohol solvents such as methanol, ethanol, and 2-propanol; halogenated hydrocarbon solvents such as dichloromethane; and acetone. , methyl ethyl ketone, etc., and a mixed solvent of two or more thereof may be used. Heating may also be used to dissolve the apixaban drug substance and the crystallization inhibitor in the solvent.

The method of distilling off the solvent is not particularly limited as long as it can make apixaban amorphous, and examples thereof include distillation under reduced pressure and spray drying.

The amount of the crystallization inhibitor to be used may be appropriately adjusted within a range where apixaban can be made amorphous, and for example, it can be 2-fold mass or more and 50-fold mass or less relative to apixaban. The ratio is preferably 3 times by mass or more, preferably 30 times by mass or less, more preferably 20 times by mass or less, and even more preferably 15 times by mass or less.

A cooled mixed melt of apixaban and a crystallization inhibitor, or a product obtained by concentrating a solution containing apixaban and a crystallization inhibitor, are usually lumps, so they should be crushed and then granulated. is preferred. The powder obtained by spray-drying the solution is also preferably sized to a desired particle size. For example, the volume-based cumulative 50% particle diameter (D ₅₀ ) of the sized amorphous apixaban powder containing the crystallization inhibitor can be 30 μm or more and 1000 μm or less.

Amorphous apixaban sized powder containing a crystallization inhibitor may be coated. Film-forming agents for coating include, for example, ethyl cellulose, talc, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, shellac, zein, and two or more of these. A mixture of
The sized amorphous apixaban powder may be coated by a conventional method. For example, the amorphous apixaban sized powder may be fluidized or rolled while being sprayed with a solution or dispersion containing a film-forming agent, dried, and then pulverized. The coated amorphous apixaban sized powder may also be further sized, for example, so that the volume-based cumulative 50% particle diameter ( _D50 ) is about 30 μm or more and 1000 μm or less.

The apixaban-containing pharmaceutical composition according to the present invention may contain general additives blended in pharmaceutical preparations. Examples of additives include excipients, disintegrants, binders, lubricants, fluidizing agents, surfactants, sweeteners, flavors and the like.

An excipient is an additive compounded to dilute a medicinal ingredient or increase the volume of a formulation in order to improve the formability and ease of administration of the formulation. Excipients include, for example, lactose, crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, mannitol, dextrin, white sugar and the like. The amount of the excipient may be adjusted as appropriate. Moreover, 70 mass % or less is preferable and 60 mass % or less is more preferable.

A disintegrant is a component that is blended to facilitate the disintegration of a tablet by taking in water and facilitating the release of active ingredients. The disintegrant is not particularly limited, but examples include croscarmellose sodium, starch, sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose (carboxymethylcellulose), carboxymethylcellulose calcium, light anhydrous silicic acid, crospovidone (crosslinked polyvinyl pyrrolidone) and the like. The amount of the disintegrant may be appropriately adjusted within a range in which the formulation can be well disintegrated after administration and the active ingredient can be released. For example, it can be 5% by mass or more and 30% by mass or less, preferably 10% by mass or more and 25% by mass or less, relative to the entire formulation.

Binders are ingredients added to bind the ingredients together and increase the strength of the granules and tablets. The binder is not particularly limited, but for example, hypromellose (hydroxypropylmethylcellulose), hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, ethylcellulose, and the like can be used. The amount and ratio of the binder in the preparation may be appropriately adjusted according to the desired preparation strength, granule strength, and the like. For example, it can be 0.1% by mass or more and 10% by mass or less with respect to the entire formulation. The ratio is preferably 0.5% by mass or more, more preferably 1% by mass or more, still more preferably 2% by mass or more, and preferably 5% by mass or less.

A lubricant is a component that is added to adhere to the surface of each component to increase its fluidity or to suppress the adhesion of each component to the device. The lubricant is not particularly limited, but for example, magnesium stearate, talc, hydrogenated vegetable oil, polyglycerin fatty acid ester, sucrose fatty acid ester, sodium stearyl fumarate, etc. can be used, and magnesium stearate is preferred. The amount and ratio of the lubricant may be appropriately adjusted, for example, within a range in which each component can be well mixed and tableted. For example, it can be 0.05% by mass or more and 5% by mass or less with respect to the entire formulation. The ratio is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and preferably 4% by mass or less, and more preferably 2% by mass or less.

The fluidizing agent is a component that enhances the fluidity of each component to promote uniform mixing of the components, and examples thereof include light silicic anhydride. The amount and ratio of the glidant may be appropriately adjusted within a range in which, for example, each component can be well mixed and tableted. can. The ratio is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and preferably 4% by mass or less, and more preferably 2% by mass or less.

Sweeteners and flavoring agents may be blended in a small amount within a range in which the effects of each component, particularly apixaban, which is a medicinal ingredient, are not inhibited and the respective effects are exhibited.

Although the dosage form of the apixaban-containing pharmaceutical composition according to the present invention is not particularly limited, examples thereof include tablets, fine granules, and dry syrup. As for tablets, granules containing the active ingredient apixaban and other ingredients such as lubricants are mixed and compressed into tablets, as well as granules containing active ingredients and rapidly disintegrating granules. , and an orally disintegrating tablet which is a compression molded body containing a lubricant-containing mixture. Fine granules are mainly composed of granules containing apixaban. Dry syrup is to be taken by dispersing it in water.

The active ingredient-containing granules contained in the orally disintegrating tablet according to the present invention may contain excipients, disintegrants, binders, surfactants and the like in addition to the active ingredient apixaban. The size of the active ingredient-containing granules may be adjusted as appropriate. For example, the volume-based cumulative 50% particle diameter (D ₅₀ ) can be 30 μm or more and 300 μm or less, preferably 50 μm or more and 200 μm or less.

The rapidly disintegrating granules contained in the orally disintegrating tablet according to the present invention absorb moisture in the oral cavity to rapidly promote the disintegration of the orally disintegrating tablet according to the present invention, thereby accelerating the release of the active ingredient apixaban. granules for Rapidly disintegrating granules contain at least an excipient and a disintegrant.

The lubricant-containing mixture contained in the orally disintegrating tablet according to the present invention contains a lubricant, promotes good mixing of the active ingredient-containing granules and the rapidly disintegrating granules, and facilitates tableting of these mixtures. It is intended to be The lubricant-containing mixture contains at least a lubricant, and may also contain excipients, fluidizing agents, sweeteners, flavors, and the like.

Although the water content of the apixaban-containing pharmaceutical composition according to the present invention is not particularly limited, it is preferably, for example, 2% by mass or less, more preferably 1% by mass or less. The lower limit of the water content is not particularly limited, and may be 0% by mass, but the water content may be, for example, 0.2% by mass or more. The water content can be measured, for example, by the Karl Fischer method.

When the apixaban-containing pharmaceutical composition according to the present invention is a tablet such as an orally disintegrating tablet, its hardness is not particularly limited. more preferred. The hardness can be adjusted, for example, by tableting pressure.

When the apixaban-containing pharmaceutical composition according to the present invention is an orally disintegrating tablet, the disintegration time is not particularly limited, but is preferably 90 seconds or less, more preferably 60 seconds or less.

The apixaban-containing pharmaceutical composition according to the present invention can be produced by a general method depending on its dosage form. For example, in the case of tablets, after apixaban is amorphous using a crystallization inhibitor as described above, amorphous apixaban is mixed with additives such as excipients and lubricants, and then tableted. .

In the case of tablets such as orally disintegrating tablets, the size of the tablet may be appropriately adjusted. For example, the shape of the tablet should be disc-shaped or lens-shaped for easy oral administration, and the diameter should be 4 mm or more and 10 mm or less, the thickness should be 2 mm or more and 5 mm or less, and the weight per tablet should be about 50 mg or more and 360 mg or less. can do.

The dosage of the apixaban-containing pharmaceutical composition according to the present invention may be appropriately adjusted according to the symptoms, severity, age, sex, etc. of the patient. 1 mg or more and 20 mg or less may be administered once or more, three times or less, or for 5 days or more and 10 days or less. In particular, for patients aged 80 years or older, patients weighing 60 kg or less, and patients with serum creatinine levels of 1.5 mg/dL or more, the dosage should be relatively low, for example, apixaban 2.5 mg twice a day. A single dose is preferred.

The apixaban-containing pharmaceutical composition according to the present invention contains, in addition to the active ingredient apixaban, one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohols, and the apixaban is amorphous. be. As a result, it has been demonstrated that the dissolution of apixaban, at least the dissolution in the stomach and the dissolution in the duodenum, is improved.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited by the following examples, and can be modified appropriately within the scope that can conform to the gist of the above and later descriptions. It is of course possible to implement them, and all of them are included in the technical scope of the present invention.

Example 1
(1) Apixaban Amorphization Apixaban drug substance (D ₅₀ : 68.2 μm, D ₉₀ : 163 μm) and polyvinylpyrrolidone (“Kollidon 30” manufactured by BASF) were mixed according to the composition shown in Table 1, and hot melt granulator. (“HAAKE ^™ MiniCTW Microconical Twin Screw Compounder 567-2090” manufactured by Thermo Fisher Scientific), melted at 180° C., and then naturally cooled to room temperature to solidify. The obtained solidified mixture was pulverized with an impact pulverizer and then sieved with a 30M sieve to obtain a sieved powder.
The obtained sieved powder was analyzed by X-ray structure diffraction together with the apixaban drug substance. The results are shown in FIG.
As shown in FIG. 1, the apixaban drug substance has clear diffraction peaks and is crystalline, whereas the sized powder obtained above does not have clear diffraction peaks. It was amorphous.

(2) Preparation of rapidly disintegrating granules With the composition shown in Table 1, lactose hydrate, ethyl cellulose, light anhydrous silicic acid, and sodium starch glycolate were placed in a fluid bed granulator and mixed. Separately, corn starch was dispersed in purified water to obtain a granulation liquid. The mixture was sprayed with a granulating liquid, dried, and then sized with a dry granule sizing machine to obtain rapidly disintegrating granules.

(3) Tableting Rapidly disintegrating granules, light anhydrous silicic acid and sodium lauryl sulfate were mixed with the composition shown in Table 1, and magnesium stearate was further mixed. The obtained mixture and the amorphous apixaban were weighed out according to the composition shown in Table 1, mixed, and tableted to obtain an apixaban-containing orally disintegrating tablet.

Example 2
Apixaban drug substance (D ₅₀ : 68.2 μm, D ₉₀ : 163 μm) and hydroxypropyl cellulose (“HPC-L” manufactured by Nippon Soda Co., Ltd.) were mixed according to the composition shown in Table 1, and a Hot Melt Granulator (“HAAKE ^TM MiniCTW Micro The mixture was placed in a conical twin-screw compounder 567-2090 (manufactured by Thermo Fisher Scientific), melted at 210° C., and then naturally cooled to room temperature to solidify. The obtained solidified mixture was pulverized with an impact pulverizer and then sieved with a 30M sieve to obtain a sieved powder.
The obtained sieved powder was analyzed by X-ray structure diffraction. The results are shown in FIG.
As shown in FIG. 1, the apixaban drug substance has clear diffraction peaks and is crystalline, whereas the sized powder obtained above does not have clear diffraction peaks. It was amorphous.
Orally disintegrating tablets containing apixaban were obtained in the same manner as in Example 1 (2) and (3), except that the obtained amorphous apixaban was used.

Example 3
Apixaban drug substance (D ₅₀ : 68.2 μm, D ₉₀ : 163 μm), polyvinylpyrrolidone (“Kollidon 30” manufactured by BASF), and isomaluhydrate were mixed with the composition shown in Table 1, and a Hot Melt Granulator (“HAAKE ^TM MiniCTW Microconical Twin Screw Compounder 567-2090 (manufactured by Thermo Fisher Scientific), melted at 180° C., and then naturally cooled to room temperature to solidify. The obtained solidified mixture was pulverized with an impact pulverizer and then sieved with a 30M sieve to obtain a sieved powder.
The obtained sieved powder was analyzed by X-ray structure diffraction. The results are shown in FIG.
As shown in FIG. 1, the apixaban drug substance has clear diffraction peaks and is crystalline, whereas the sized powder obtained above does not have clear diffraction peaks. It was amorphous.
Orally disintegrating tablets containing apixaban were obtained in the same manner as in Example 1 (2) and (3), except that the obtained amorphous apixaban was used.

Comparative example 1
Lactose hydrate, ethyl cellulose, light anhydrous silicic acid, and sodium starch glycolate having the composition shown in Table 1 were placed in a fluid bed granulator and mixed. Separately, corn starch was dispersed in purified water to obtain a granulation liquid. The mixture was sprayed with a granulating liquid, dried, and then sized with a dry granule sizing machine to obtain rapidly disintegrating granules.
Rapidly disintegrating granules, apixaban drug substance, polyvinylpyrrolidone ("Kollidon 30" manufactured by BASF), light anhydrous silicic acid, and sodium lauryl sulfate were mixed according to the composition shown in Table 1, and magnesium stearate was further mixed and beaten. By tableting, an apixaban-containing orally disintegrating tablet was obtained.

Comparative example 2
An apixaban-containing orally disintegrating tablet was obtained in the same manner as in Comparative Example 1, except that hydroxypropyl cellulose ("HPC-L" manufactured by Nippon Soda Co., Ltd.) was used in place of polyvinylpyrrolidone with the composition shown in Table 1.

Comparative example 3
An apixaban-containing orally disintegrating tablet was obtained in the same manner as in Comparative Example 1, except that polyvinylpyrrolidone (“Kollidon 30” manufactured by BASF) and isomaluhydrate were used instead of polyvinylpyrrolidone and had the composition shown in Table 1. .

Test Example 1: Dissolution Test The drug dissolution properties of the apixaban-containing orally disintegrating tablets of Examples 1 to 3 and Comparative Examples 1 to 3 were tested by the paddle method of Japanese Pharmacopoeia 6.10 Dissolution Test.
Specifically, a 10-fold diluted solution (900 mL) of dissolution test liquid 1 (pH 1.2, manufactured by Kanto Chemical Co., Ltd.) or dissolution test liquid 2 (pH 6.8, manufactured by Kanto Chemical Co., Ltd.) is placed in the dissolution tester. , the temperature of the test liquid was adjusted to 37±0.5° C., and one tablet of each tablet was added while stirring at 50 rpm. 5, 10, 15, 30, 60, and 120 minutes after the addition of the tablets when using the dissolution test fluid 1, and after an additional 240 minutes when using the dissolution test fluid 2, add 20 mL of the dissolution fluid. It was collected and filtered through a membrane filter with a diameter of 0.45 µm or less. The first 10 mL of the filtrate was removed, and the next filtrate was used as the sample solution.
Separately, about 20 mg of apixaban for quantitative determination was accurately weighed, and the test solution was added to make exactly 200 mL, which was used as a standard solution. 30 μL of the sample solution and the standard solution were accurately weighed, the apixaban peak areas A _T and A _s of each solution were measured by liquid chromatography under the following conditions, and the elution rate was calculated by the following formula. The measurement was performed 6 times for each tablet, and the average was calculated. FIG. 2 shows the results of using the first dissolution test liquid corresponding to gastric juice, and FIG. 3 shows the results of using the second dissolution test liquid corresponding to the environment in the small intestine.

[Liquid chromatography conditions]
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 10 cm filled with 3 μm octadecylsilylated silica gel for liquid chromatography Column temperature: Constant temperature around 40° C. Mobile phase: 3.6 g of disodium hydrogen phosphate in water Dissolve in 1000 mL, add phosphoric acid to adjust pH to 7.0, mix 650 mL of the resulting solution with 350 mL of acetonitrile Flow rate: Adjust retention time of apixaban to about 4.5 minutes

As the results shown in FIGS. 2 and 3 show, the dissolution of apixaban from the orally disintegrating tablets of Comparative Examples 1 to 3, which were produced using the crystalline apixaban drug substance as it was, was completely unsatisfactory.
On the other hand, the dissolution of apixaban from the orally disintegrating tablets of Examples 1 to 3, which were produced after amorphizing apixaban using a specific crystallization inhibitor, was evaluated in the first dissolution test corresponding to gastric juice. It was remarkably improved for both the liquid and the 2nd dissolution test liquid corresponding to the environment in the small intestine.
As described above, it was demonstrated that the dissolution of apixaban from the pharmaceutical composition can be significantly improved by amorphizing the active ingredient apixaban using a specific crystallization inhibitor.

Examples 4-7
(1) Apixaban Amorphization Apixaban drug substance (D ₅₀ : 40.166 μm, D ₉₀ : 108.450 μm) and hydroxypropyl cellulose (“HPC-SSL” manufactured by Nippon Soda Co., Ltd.) were prepared according to the composition shown in Table 2. Using a twin-screw extruder (“Pharma 11” manufactured by Thermo Fisher Scientific), a solid dispersion was produced by melt-mixing at 230° C. and then naturally cooling to room temperature. A solid dispersion powder for Example 4 was obtained by pulverizing the obtained solid dispersion with a pin mill pulverizer.

(2) Coating of Solid Dispersion Powder In Examples 5 to 7, the obtained solid dispersion powder was coated.
Specifically, purified water and 99.5% ethanol were mixed to obtain a mixed solvent. Ethyl cellulose ("Ethocel Premium 7FP", manufactured by Nutrition & Biosciences) was dissolved in the resulting mixed solvent with the composition shown in Table 2, and talc ("Tarkan Hayashi", manufactured by Hayashi Kasei Co., Ltd.) was dispersed to obtain a coating liquid. .
The solid dispersion powder was put into a fluid bed granulator dryer, coated with a coating liquid, dried, and then sized with a dry granulator to obtain a sized powder.

(3) Preparation of rapidly disintegrating granules With the composition shown in Table 2, lactose hydrate, ethyl cellulose, light anhydrous silicic acid, and sodium starch glycolate were placed in a fluid bed granulator and mixed. Separately, corn starch was dispersed in purified water to obtain a granulation liquid. The mixture was sprayed with a granulating liquid, dried, and then sized with a dry granule sizing machine to obtain rapidly disintegrating granules.

(4) Tableting Coated powder, rapidly disintegrating granules, light anhydrous silicic acid and magnesium stearate were mixed with the composition shown in Table 2 and tableted to obtain orally disintegrating tablets containing apixaban.

Test Example 2: Dissolution Test Liquid 1 for dissolution test (pH 1.2, manufactured by Kanto Kagaku Co., Ltd.) was used in a dissolution tester, and the apixaban-containing orally disintegrating tablets of Examples 4 to 7 were tested under the same conditions as in Test Example 1. Drug elution was tested. The results are shown in FIG.

As shown in the results shown in FIG. 4, as long as the apixaban is made amorphous, there is a tendency that the smaller the amount of coating, the higher the dissolution. was done. When the coating amount was 10% by mass or more, there was no difference in the dissolution properties between the 10% by mass formulation (Example 6) and the 20% by mass formulation (Example 7). One possible reason for this is that the core particles are not spherical but have a distorted shape, which prevents uniform coating.

Example 8
Apixaban-containing orally disintegrating tablets were produced in the same manner as in Examples 5 to 7, except that the composition was as shown in Table 3.

Example 9
(1) Apixaban Amorphization Apixaban drug substance (D ₅₀ : 40.166 μm, D ₉₀ : 108.450 μm) and hydroxypropyl cellulose ("HPC-SSL" manufactured by Nippon Soda Co., Ltd.) were prepared according to the composition shown in Table 4. Using a twin-screw extruder (“Pharma 11” manufactured by Thermo Fisher Scientific), a solid dispersion was produced by melt-mixing at 230° C. and then naturally cooling to room temperature. The obtained solid dispersion was pulverized with a pin mill pulverizer to obtain a solid dispersion powder.

(2) Coating of solid dispersion powder Purified water and 99.5% ethanol were mixed to obtain a mixed solvent. Ethyl cellulose ("Ethocel Premium 7FP", manufactured by Nutrition & Biosciences) was dissolved in the obtained mixed solvent with the composition shown in Table 4, and talc ("Tarkan Hayashi", manufactured by Hayashi Kasei Co., Ltd.) was dispersed to obtain a coating liquid I. rice field.
The solid dispersion powder was charged into a fluidized bed granulator dryer, coated with coating liquid I, dried, and then granulated with a dry granulator to obtain coated granulated powder I.
Furthermore, aminoalkyl methacrylate copolymer E was dissolved in the mixed solvent, and talc ("Tarukan Hayashi" manufactured by Hayashi Kasei Co., Ltd.) was dispersed to obtain Coating Liquid II.
Coated sieved powder I was fed into a fluidized bed granulator dryer, coated with coating liquid II, dried, and then sized with a dry sizing machine to obtain coated sieved powder II.

(3) Preparation of rapidly disintegrating granules With the composition shown in Table 4, lactose hydrate, ethyl cellulose, light anhydrous silicic acid, and sodium starch glycolate were placed in a fluid bed granulator and mixed. Separately, corn starch was dispersed in purified water to obtain a granulation liquid. The mixture was sprayed with a granulating liquid, dried, and then sized with a dry granule sizing machine to obtain rapidly disintegrating granules.

(4) Tableting Apixaban-containing orally disintegrating tablets were obtained by mixing coated powder II, rapidly disintegrating granules, light anhydrous silicic acid and magnesium stearate according to the composition shown in Table 4 and tableting. .

Example 10
(1) Apixaban Amorphization Apixaban drug substance (D ₅₀ : 40.166 μm, D ₉₀ : 108.450 μm) and hydroxypropyl cellulose (“HPC-SSL” manufactured by Nippon Soda Co., Ltd.) with the composition shown in Table 5 were Using a twin-screw extruder (“Pharma 11” manufactured by Thermo Fisher Scientific), a solid dispersion was produced by melt-mixing at 230° C. and then naturally cooling to room temperature. The obtained solid dispersion was pulverized with a pin mill pulverizer to obtain a solid dispersion powder.

(2) Coating of Solid Dispersion Powder Purified water and 99.5% ethanol were mixed at a ratio of 17:150 (mass ratio) to obtain a mixed solvent. Ethyl cellulose ("Ethocel Premium 7FP", manufactured by Nutrition & Biosciences) was dissolved in the resulting mixed solvent with the composition shown in Table 5, and talc ("Talcan Hayashi", manufactured by Hayashi Kasei Co., Ltd.) was dispersed to obtain a coating liquid. .
The solid dispersion powder was charged into a fluidized bed granulator dryer, coated with a coating liquid, dried, and then granulated with a dry granulator to obtain coated granulated powder.

(3) Tableting Lactose hydrate, crystalline cellulose, corn starch, croscarmellose sodium and magnesium stearate were mixed according to the composition shown in Table 5. The obtained mixture and the coated sized powder were weighed out according to the composition shown in Table 5, mixed, and tableted to obtain apixaban tablets.

Claims (9)

A method for improving the dissolution of apixaban from a pharmaceutical composition containing apixaban as a medicinal ingredient, comprising:
A method comprising amorphizing said apixaban with one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohols. 2. The method of claim 1, wherein the apixaban is amorphized by heating the mixture of the apixaban and the crystallization inhibitor to melt and then cooling. 2. The method of claim 1, wherein said pharmaceutical composition is a tablet. 4. The method of claim 3, further comprising mixing and tableting the apixaban, rapid disintegrating granules, and lubricant-containing mixture that has been amorphized. The method according to any one of claims 1 to 4, wherein polyvinylpyrrolidone is used as the crystallization inhibitor. 6. The method of claim 5, wherein a sugar alcohol is used in addition to polyvinylpyrrolidone as the crystallization inhibitor. The method according to any one of claims 1 to 4, wherein hydroxypropylcellulose is used as the crystallization inhibitor. Contains the medicinal ingredients apixaban and a crystallization inhibitor,
The apixaban is amorphous, and
A pharmaceutical composition, wherein the crystallization inhibitor is one or more selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohol. A method for producing a pharmaceutical composition containing apixaban as a medicinal ingredient, comprising:
A method comprising amorphizing said apixaban with one or more crystallization inhibitors selected from polyvinylpyrrolidone, hydroxypropylcellulose, and sugar alcohols.

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