Apixaban-containing composition, apixaban-containing solid preparation, and method for producing apixaban-containing solid preparation.

Abstract

This invention provides a solid preparation containing apixaban that exhibits stable dissolution properties and suppresses the formation of related substances, a method for producing the solid preparation, and an apixaban-containing composition that serves as a raw material for the solid preparation. [Solution] An apixaban-containing composition comprising crystalline apixaban particles, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent; and a dispersion preparation step of preparing a dispersion containing crystalline apixaban particles and a surfactant; a granulation step of granulating the dispersion and an excipient as raw materials after the dispersion preparation step; and a formulation step of manufacturing a solid preparation using the obtained granulated powder as raw materials after the granulation step, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent.

Description

[Technical Field]

[0001] The present invention relates to a novel apixaban-containing solid dosage form, a method for producing the same, and an apixaban-containing composition that serves as a raw material for the apixaban-containing solid dosage form. [Background technology]

[0002] Apixaban is marketed as an anticoagulant under the name Eliquis® tablets. Apixaban is a poorly water-soluble drug and is not well absorbed from the gastrointestinal tract, so formulation modifications are necessary to improve its absorption.

[0003] To address these challenges, for example, Patent Document 1 discloses a composition comprising crystalline apixaban particles having an average particle size equivalent to or less than approximately 89 μm, and a pharmaceutically acceptable diluent or carrier. Patent Document 2 discloses a sustained-release agent using a solid amorphous dispersion containing amorphous apixaban and a polymer selected from hydroxypropyl methylcellulose (hypromellose) or hydroxypropyl methylcellulose succinate acetate. Patent Document 3 reports an apixaban solid dispersion containing apixaban and a carrier different from that in Patent Document 2, such as polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer. Patent Document 4 discloses a solid dispersion in which the amorphous agent is present in a weight ratio greater than 0% but less than 100% of the total amount of apixaban.

[0004] However, in the formulations using solid dispersions of apixaban described in Patent Documents 2 or 3, an excessive amount of polymer is used relative to the apixaban, resulting in a large formulation that is difficult for elderly people and children with difficulty swallowing to take. Furthermore, in the solid dispersion formulations described in Patent Documents 2 to 4, it is necessary to ensure the stability of amorphous apixaban, and if a transition from amorphous to crystalline occurs, there are concerns about problems such as the effect on dissolution. In addition, Patent Document 5 discloses that reducing the particle size of apixaban makes it easier to generate related substances from apixaban, and proposes a pharmaceutical composition containing apixaban with different particle sizes having a bimodal particle size distribution including a first peak and a second peak in the particle size distribution measured by laser light scattering. However, when compositions with different particle sizes are made into tablets in general, good uniformity of content may not be obtained due to segregation or other factors during the manufacturing process. If the content is not uniform, patients may be administered an overdose or underdose of the active ingredient, which could increase the risk of insufficient efficacy or side effects. Therefore, formulations exhibiting good content uniformity are desirable. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Special Publication No. 2013-521226 [Patent Document 2] Patent No. 5775071 [Patent Document 3] Japanese Patent Publication No. 2021-152005 [Patent Document 4] Japanese Patent Publication No. 2023-121748 [Patent Document 5] Japanese Patent Publication No. 2024-064876 [Overview of the project] [Problems that the invention aims to solve]

[0006] To produce a solid dosage form that exhibits more stable dissolution behavior, it is preferable to use crystalline apixaban as the active ingredient rather than amorphous apixaban. On the other hand, reducing the particle size to improve the dissolution and absorption from the gastrointestinal tract of crystalline apixaban, which is a poorly water-soluble drug, tends to generate related substances. Therefore, a formulation that exhibits stable dissolution behavior and suppresses the generation of related substances is desired.

[0007] Therefore, the present invention relates to providing an apixaban-containing solid preparation that exhibits stable dissolution properties and suppresses the generation of related substances, a method for producing the solid preparation, and an apixaban-containing composition that serves as a raw material for the solid preparation. [Means for solving the problem]

[0008] As a result of diligent research to solve the problem, the inventors of the present invention discovered that by using crystalline apixaban, which has been formed into primary particles together with a swelling agent, as a raw material, it is possible to produce a solid dosage form that exhibits stable dissolution behavior and suppresses the formation of related substances, thus completing the present invention.

[0009] The present invention encompasses the following embodiments. [1] A apixaban-containing composition comprising crystalline apixaban particles, An apixaban-containing composition in which the primary particles of the crystalline apixaban particles contain crystalline apixaban and a swelling agent. [2] The apixaban-containing composition of [1], wherein the swelling agent is a substance that functions as a disintegrant. [3] The apixaban-containing composition according to [1] or [2], wherein the content ratio (by mass) of crystalline apixaban to a swelling agent is 1:0.1 to 1:10. [4] Furthermore, an apixaban-containing composition according to any of [1] to [3], which also contains a surfactant. [5] A powdered apixaban-containing composition according to any of [1] to [4] above. [6] A dispersion of any of the apixaban-containing compositions described in [1] to [4] above. [7] A dispersion preparation step of preparing a dispersion containing crystalline apixaban particles and a surfactant, After the dispersion preparation step, a granulation step of granulating the dispersion and an excipient as raw materials, After the granulation step, a formulation step of manufacturing a solid preparation using the obtained granulated powder as a raw material, having A method for producing an apixaban-containing solid preparation, wherein at least a part of the primary particles of the crystalline apixaban particles in the dispersion contains crystalline apixaban and a swelling agent. [8] The method for producing an apixaban-containing solid preparation according to [7] above, wherein the swelling agent is a substance that functions as a disintegrant. [9] The method for producing an apixaban-containing solid preparation according to [7] or [8] above, wherein the content ratio (mass) of crystalline apixaban to the swelling agent in the dispersion is 1:0.1 to 1:10.

[10] The method for producing an apixaban-containing solid preparation according to any one of [7] to [9] above, wherein the solid preparation is a tablet.

[11] An apixaban-containing solid preparation containing crystalline apixaban particles, An apixaban-containing solid preparation, wherein the primary particles of the crystalline apixaban particles contain crystalline apixaban and a swelling agent.

[12] The apixaban-containing solid preparation according to

[11] above, wherein the swelling agent is a substance that functions as a disintegrant.

[13] The apixaban-containing solid preparation according to

[11] or

[12] above, wherein the content ratio (mass) of crystalline apixaban to the swelling agent in the crystalline apixaban particles is 1:0.1 to 1:10.

Advantages of the Invention

[0010] According to the present invention, an apixaban-containing solid preparation excellent in stability and dissolution properties can be provided. Further, the present invention can provide an apixaban-containing composition suitable as a raw material for producing the apixaban-containing solid preparation.

Brief Description of the Drawings

[0011] [Figure 1]This is a diagram showing the results of the dissolution test in water of the apixaban-containing tablets of Example 2 and Comparative Example 1. [Figure 2] This is a diagram showing the results of the dissolution test in the second dissolution test solution of the apixaban-containing tablets of Example 2 and Comparative Example 1.

Mode for Carrying Out the Invention

[0012] <Apixaban-containing Composition> The apixaban-containing composition of the present embodiment is a composition containing crystalline apixaban particles, and the primary particles of the crystalline apixaban particles contain crystalline apixaban and a swelling agent. Since the active ingredient apixaban in the apixaban-containing composition of the present embodiment is crystalline particles, it has excellent stability. In addition, in the apixaban-containing composition of the present embodiment, at least a part of the primary particles of the crystalline apixaban particles in the composition contains a swelling agent, so that when it is contained in a solid preparation, both the dissolution property and the content uniformity of apixaban are good, and a solid preparation with little generation of related substances can be obtained.

[0013] In the present invention and the present specification, "crystalline apixaban particles" means particles containing crystalline apixaban, and unless otherwise specified, in addition to particles consisting only of crystalline apixaban, particles containing crystalline apixaban and other substances are also included. Further, "crystalline apixaban particles" include not only primary particles but also secondary particles (aggregates of primary particles) and particles obtained by granulation.

[0014] The crystalline apixaban used in the present embodiment is not particularly limited. For example, crystalline apixaban produced by a known method such as the methods described in International Publication No. 2006 / 13542 and International Publication No. 2007 / 001385 can be used. In the present embodiment, the particle diameter of the crystalline apixaban particles used as raw materials is not particularly limited. For example, the particle diameter D 90However, apixaban with a size of 10 μm to 500 μm can be used, preferably in the range of 30 μm to 400 μm, more preferably 50 μm to 350 μm, and even more preferably 100 μm to 300 μm.

[0015] The swelling agent used in this embodiment is not particularly limited, and various swelling agents used in the manufacture of pharmaceuticals can be used. The swelling agent used in this embodiment may be one type, or two or more types may be used in combination.

[0016] In order to improve the dissolution and uniformity of apixaban content, the swelling agent used in this embodiment is preferably a substance that functions as a disintegrant. Examples of swelling agents that function as disintegrants include carmellose (carboxymethylcellulose), crystalline cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, and low-substituted hydroxypropylcellulose.

[0017] The swelling agent used in this embodiment may be a substance that does not function as a disintegrant. Examples of such substances include polysaccharides such as oligosaccharides, cellulose, glycogen, dextran, pullulan, and gellan gum; phospholipids such as soy lecithin and hydrogenated soy phospholipids; polymers such as agar, gelatin, succinylated gelatin, karaya gum powder, and carboxyvinyl polymer; and starches such as partially pregelatinized starch, starch acrylate 300, starch acrylate 1000, pregelatinized starch, corn starch, potato starch, rice starch, and wheat starch.

[0018] The content ratio (by mass) of crystalline apixaban to swelling agent in the crystalline apixaban particles in the apixaban-containing composition of this embodiment is not particularly limited, and for example, crystalline apixaban:swelling agent can be 1:0.1 to 1:10 (by mass). From the viewpoint of suitability for the manufacture of solid dosage forms with a higher apixaban content, the content ratio (crystalline apixaban:swelling agent) of crystalline apixaban to swelling agent (crystalline apixaban:swelling agent) is preferably 1:0.1 to 1:7 (by mass), more preferably 1:0.2 to 1:5 (by mass), even more preferably 1:0.3 to 1:3 (by mass), and even more preferably 1:0.3 to 1:1 (by mass).

[0019] The particle size of the crystalline apixaban particles in the apixaban-containing composition of this embodiment is not particularly limited, for example, particle size D 90 The particle size D of crystalline apixaban particles in the apixaban-containing composition of this embodiment 90 In terms of suppressing the formation of related substances, a particle size of 90 μm to 500 μm is preferred, more preferably 100 μm to 500 μm, even more preferably 100 μm to 400 μm, and even more preferably 100 μm to 300 μm.

[0020] "Particle size D of crystalline apixaban" 90 " refers to the particle size D of crystalline apixaban particles. 90 Therefore, the particle diameter D of the entire particle, including not only primary particles but also secondary particles, is... 90 This represents the particle size of crystalline apixaban. Note that the particle size of crystalline apixaban is the volume-based particle size (the diameter of a sphere with the same volume as the particle is defined as the particle size of the particle). 90 This can be measured, for example, using a wet-type laser diffraction / scattering particle size distribution analyzer.

[0021] The apixaban-containing composition of this embodiment may consist only of crystalline apixaban particles, or it may contain other components in addition to crystalline apixaban particles. If the apixaban-containing composition of this embodiment contains components other than crystalline apixaban particles, the ratio of crystalline apixaban particles to the total solid content of the composition is preferably 60% by mass or more, more preferably 70% by mass or more, and even more preferably 75% by mass or more.

[0022] The apixaban-containing composition of this embodiment may be in powder or dispersion form. The solvent for the dispersion is not particularly limited and includes water, methanol, ethanol, isopropanol, and other lower alcohols. Water is particularly preferred from a safety standpoint.

[0023] If the apixaban-containing composition of this embodiment is a dispersion, the dispersion may contain a surfactant. The surfactant used is not particularly limited, and various surfactants used in the manufacture of pharmaceuticals can be used. Specifically, examples include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer. The surfactant used in this embodiment may be one type or a combination of two or more types. Sodium lauryl sulfate is particularly preferred as the surfactant used in this embodiment because it can improve the elution and uniformity of apixaban content, and can also more sufficiently suppress the generation of related substances.

[0024] If the apixaban-containing composition of this embodiment contains components other than crystalline apixaban particles, such components are not particularly limited as long as they do not affect the effects of the present invention, and include various components that are commonly used as pharmaceutical additives. For example, the apixaban-containing composition of this embodiment may contain pharmaceutical additives described later (excipients, lubricants, plasticizers, binders, disintegrants, fluidizers, colorants, antistatic agents, etc.).

[0025] Crystalline apixaban particles, in which the primary particles contain crystalline apixaban and a swelling agent, can be produced, for example, from crystalline apixaban and a swelling agent by the method described in Example 1 below or a similar method.

[0026] <Method for manufacturing apixaban-containing solid preparations> The method for producing an apixaban-containing solid dosage form according to this embodiment is a method for producing a solid dosage form containing crystalline apixaban particles, characterized in that crystalline apixaban particles are prepared in which at least a portion of the primary particles of the crystalline apixaban particles contain crystalline apixaban and a swelling agent, and these are used as a granulation raw material. By this method, an apixaban-containing solid dosage form containing crystalline apixaban particles in which at least a portion of the primary particles contain crystalline apixaban and a swelling agent can be produced.

[0027] The method for producing an apixaban-containing solid dosage form according to this embodiment is a method for producing an apixaban-containing solid dosage form containing crystalline apixaban, and comprises the following steps. A dispersion preparation step, comprising preparing a dispersion containing crystalline apixaban, a swelling agent, and a surfactant. A granulation step, which is performed after the dispersion preparation step using the dispersion and the excipient as raw materials. A formulation process in which, after the granulation process, the obtained granules are used as a raw material to produce a solid dosage form.

[0028] The crystalline apixaban, swelling agent, and surfactant used as raw materials in the dispersion preparation step can be the same as those used in the apixaban-containing composition of this embodiment. The swelling agent used in the dispersion preparation step is preferably a substance that functions as a disintegrant, and more preferably one or more selected from the group consisting of carmellose, crystalline cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose. The surfactant used in the dispersion preparation step is preferably one or more selected from the group consisting of sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer, with sodium lauryl sulfate being particularly preferred.

[0029] The ratio (by mass) of crystalline apixaban and swelling agent used as raw materials in the dispersion preparation process is not particularly limited. For example, the ratio of crystalline apixaban to swelling agent can be 1:0.1 to 1:10 (by mass), with 1:0.1 to 1:7 (by mass) being preferred, 1:0.2 to 1:5 (by mass), and 1:0.3 to 1:3 (by mass).

[0030] The dispersion prepared in the dispersion preparation step contains crystalline apixaban, a swelling agent, and a surfactant, and at least a portion of the primary particles of the crystalline apixaban particles in the dispersion contain crystalline apixaban and the swelling agent. In the method for producing apixaban-containing solid dosage forms of a given embodiment, by using crystalline apixaban particles in which at least a portion of the primary particles contain the swelling agent as raw materials, it is possible to produce apixaban-containing solid dosage forms that are excellent in apixaban stability, dissolution and content uniformity, and have a very low content of related substances.

[0031] Particle size D of crystalline apixaban particles in the dispersion prepared in the dispersion preparation step 90In terms of suppressing the formation of related substances in the manufactured apixaban-containing solid dosage form, the particle size is preferably 90 μm to 500 μm, more preferably 100 μm to 500 μm, even more preferably 100 μm to 400 μm, and even more preferably 100 μm to 300 μm.

[0032] In the dispersion preparation process, a dispersion containing crystalline apixaban particles and a surfactant, where the primary particles are crystalline apixaban and a swelling agent, can be prepared, for example, by adding crystalline apixaban, a swelling agent, and a surfactant to an aqueous medium and dispersing the resulting suspension using a mixing machine. The type and conditions of the mixing machine used can be set as appropriate.

[0033] The type of aqueous medium used in the dispersion preparation step is not particularly limited, and for example, water, methanol, ethanol, isopropanol, or a mixture of two or more of these solvents can be used, with water being preferred.

[0034] The dispersion preparation step can be carried out, for example, by the methods of steps 1 and 2 described in Example 1 below, and by methods similar thereto.

[0035] In the granulation process, the dispersion prepared in the dispersion preparation process and the excipient are used as raw materials for granulation. Examples of granulation methods include dry granulation and wet granulation. Wet granulation methods include agitation granulation, tumbling granulation, and fluidized bed granulation. In this embodiment, the method for producing the apixaban-containing solid dosage form is preferably granulated by wet granulation, and more preferably by fluidized bed granulation or agitation granulation. In the wet granulation method, the dispersion, the excipient, and other additives as needed are mixed in the presence of a liquid such as water or ethanol, and the granulation described above is performed.

[0036] During granulation, in addition to the dispersion and excipient, other additives may be added as needed. Examples of such additives include lubricants, plasticizers, binders, disintegrants, fluidizers, surfactants, light-shielding agents, pH adjusters, coating agents, colorants, and antistatic agents. These can be used individually or in combination of two or more.

[0037] Excipients include, for example, sugars such as lactose, sucrose, trehalose, and glucose; sugar alcohols such as D-mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, and xylitol; and crystalline cellulose, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, etc., with lactose, sugar alcohols, or crystalline cellulose being preferred.

[0038] Lubricant: For example, talc, glyceryl monostearate, macrogol, magnesium stearate, calcium stearate, or sodium stearyl fumarate, preferably talc, glyceryl monostearate, magnesium stearate, calcium stearate, or sodium stearyl fumarate, most preferably magnesium stearate.

[0039] Plasticizers include, for example, polyethylene glycol (e.g., polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, etc.), triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, sorbitan monolaurate, sorbitan monostearate, glycerin, castor oil, polyoxyethylene hydrogenated castor oil, polysorbate 80, poloxamer, macrogol, lauromacrogol, propylene glycol, triacetin, etc., with triethyl citrate being preferred.

[0040] Binders: Examples include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, macrogol, Pluronic F68, gum arabic, gelatin, starch, etc. Preferably, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose are used, and more preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose are used.

[0041] Disintegrants include, for example, starches such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose (carboxymethylcellulose), carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose, and hydroxypropyl starch.

[0042] Fluidizing agents include, for example, talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, and magnesium stearate.

[0043] Surfactants include, for example, sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer.

[0044] Light-blocking agent: Examples include titanium dioxide, zinc oxide, talc, iron oxides such as yellow iron(III) oxide, iron(III) oxide, and black iron oxide, food yellow No. 5, food red No. 102, and titanium dioxide is preferred.

[0045] Coating agents include, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and methacrylic acid copolymer.

[0046] Coloring agents include, for example, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Red No. 2, Food Red No. 3, Food Blue No. 1 aluminum lake, Food Blue No. 2 aluminum lake, Food Red No. 2 aluminum lake, iron(III) oxide (red), titanium dioxide, yellow iron(III) oxide, caramel, talc, etc.

[0047] Antistatic agents include, for example, silicon dioxide (including hydrated silicon dioxide), anhydrous silicon, talc, titanium dioxide, stearic acid, magnesium stearate, and calcium stearate.

[0048] The mixing of various raw materials before granulation can be carried out using commonly used mixing methods. Specifically, mixing can be done using, for example, a high-speed agitator, a universal mixer, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double-cone mixer, a ribbon mixer, a swirling screw mixer, or manual mixing in bags.

[0049] The granulation process can be carried out, for example, by the methods of steps 3 and 4 described in Example 1 below, and by methods similar thereto.

[0050] Subsequently, in the formulation process, a solid dosage form is manufactured using the granulated powder obtained in the granulation process as a raw material. The solid dosage form can be various types, such as tablets, granules, or capsules.

[0051] The granulated powder obtained in the granulation process may be used in the manufacture of solid dosage forms after drying. The drying process can be carried out using general drying methods such as hot air drying.

[0052] Tablets are particularly preferred as the solid dosage form produced in this embodiment. Tablets can be produced by compression molding of granulated powder and, if necessary, other pharmaceutical additives. The resulting tablets may be film-coated by a generally known method if necessary.

[0053] Compression molding can be performed using rotary tablet presses or the like commonly used in pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet, but for example, for a φ10mm tablet, it is 2 to 10kN, preferably 3 to 9kN, and for a φ8.5mm tablet, it is 2 to 6kN, preferably 3 to 5kN. At this time, the set hardness is 30 to 200N, preferably 40 to 180N, and more preferably 50 to 150N.

[0054] The formulation process can be carried out, for example, by the methods of steps 5 and 6 described in Example 1 below, and by methods similar thereto.

[0055] <Apixaban-containing solid preparation> The apixaban-containing solid preparation of this embodiment is an apixaban-containing solid preparation containing crystalline apixaban particles, wherein the primary particles of the crystalline apixaban particles contain crystalline apixaban and a swelling agent. That is, the apixaban-containing solid preparation of this embodiment is a solid preparation manufactured using the apixaban-containing composition of this embodiment as a raw material, and the crystalline apixaban particles in the preparation are the same as the crystalline apixaban particles in the apixaban-containing composition of this embodiment. The apixaban-containing solid preparation of this embodiment can be manufactured by the method for manufacturing the apixaban-containing solid preparation of this embodiment described above.

[0056] The swelling agent contained in the crystalline apixaban particles in the apixaban-containing solid preparation of this embodiment can be the same as the crystalline apixaban and swelling agent used in the apixaban-containing composition of this embodiment described above. The swelling agent is preferably a substance that functions as a disintegrant, and more preferably one or more selected from the group consisting of carmellose, crystalline cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose.

[0057] The mass ratio of crystalline apixaban to the swelling agent in the crystalline apixaban particles in the apixaban-containing solid preparation of the present embodiment is not particularly limited. For example, the ratio of crystalline apixaban:swelling agent can be 1:0.1 to 1:10 (mass ratio), preferably 1:0.1 to 1:7 (mass ratio), more preferably 1:0.2 to 1:5 (mass ratio), and even more preferably 1:0.3 to 1:3 (mass ratio).

[0058] The particle size D of the crystalline apixaban particles in the apixaban-containing solid preparation of the present embodiment 90 is preferably 90 μm or more and 500 μm or less, more preferably 100 μm or more and 500 μm or less, even more preferably 100 μm or more and 400 μm or less, and still more preferably 100 μm or more and 300 μm or less from the viewpoint of suppressing the formation of related substances.

[0059] The apixaban-containing solid preparation of the present embodiment contains crystalline apixaban particles containing a swelling agent in primary particles, and thus is excellent in all of stability, elution property, and content uniformity, and the content of related substances is also sufficiently reduced. When the apixaban-containing solid preparation of the present embodiment is a tablet, the content uniformity of apixaban can be measured by the method described in the following examples. When the apixaban-containing solid preparation of the present embodiment is a tablet, the elution property of apixaban can be measured by the following method.

[0060] (Measurement of elution property) Using the first elution test solution (pH 1.2) prepared by dissolving 2.0 g of sodium chloride in 7.0 mL of hydrochloric acid and water to make 1000 mL, the elution property is measured by the paddle method under the condition of 50 rpm, except for the method of the elution test in the Japanese Pharmacopoeia.

[0061] The elution property of apixaban in the tablet, which is the apixaban-containing solid preparation of the present embodiment, is preferably 60% or more in 10 minutes.

[0062] Although preferred embodiments of the present invention have been described above, the present invention is not limited to these examples. The combinations shown in the above examples are merely examples, and various modifications can be made based on design, specifications, etc., without departing from the spirit of the present invention. [Examples]

[0063] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0064] [Example 1] Through the following process, crystalline apixaban particles containing crystalline apixaban and a swelling agent were produced as primary particles, and tablets, which are apixaban-containing solid dosage forms, were manufactured using these as raw materials.

[0065] [Step 1] Crystalline apixaban (D 90 10g of (149μm) and 5g of carmellose were added to 50g of purified water and dispersed using a mixing machine (Primix Corporation: Lab Solution®) to obtain a dispersion. The particle size D of the particles in the dispersion was 90 It was 120 μm. [Step 2] 4 g of sodium lauryl sulfate was added to the dispersion and dissolved. [Step 3] 306 g of anhydrous lactose, 4 g of hydroxypropyl methylcellulose, and 60 g of crystalline cellulose were placed in a stirring granulator (Powrec Co., Ltd.: VG-01) and mixed for 5 minutes at a blade rotation speed of 400 rpm and a cross screw rotation speed of 2000 rpm. After mixing, the dispersion was added dropwise at a constant rate while granulation was performed for 6 minutes at a blade rotation speed of 400 rpm and a cross screw rotation speed of 2000 rpm to obtain granulated powder. [Step 4] The granulated powder was sized using a 30M sieve and dried in a dryer at 60°C for 2 hours to obtain a dried powder. [Step 5] The dried powder was granulated using a 30M sieve, then 8g of croscarmellose sodium and 3g of magnesium stearate were added, and the mixture was bagged and compressed to obtain tablet powder. [Step 6] The tablet powder was compressed using a Φ8×R12 punch to a set hardness of 80N to obtain tablets.

[0066] [Examples 2] to [Examples 11], [Comparative Example 1] Crystalline apixaban (D 90 Tablets were obtained in the same manner as in Example 1, except that a fluidized bed granulator (Multiplex, manufactured by Powrec Co., Ltd.) was used instead of a stirred granulator (VG-01, manufactured by Powrec Co., Ltd.) with a thickness of 114 μm, and with the compositions described in Tables 1 and 2.

[0067] [Table 1]

[0068] [Table 2]

[0069] [Test Example 1] (Leaching test) Dissolution was measured according to the dissolution test method of the 17th edition of the Japanese Pharmacopoeia, except that water and dissolution test solution 2 (pH 6.8) were used and the paddle method was set to 50 rpm. The results of the dissolution test with water for the tablets of Example 2 and Comparative Example 1 are shown in Table 3 and Figure 1, and the results of the dissolution test with dissolution test solution 2 are shown in Table 4 and Figure 2, respectively.

[0070] [Table 3]

[0071] [Table 4]

[0072] As shown in Tables 3 and 4, in dissolution tests using either water or the second dissolution test solution, the tablets of Example 2 had a higher dissolution rate than the tablets of Comparative Example 1. These test results confirmed that the apixaban-containing solid dosage form of this embodiment exhibits good dissolution properties.

[0073] [Test Example 2] (Content uniformity test) The relative standard deviation of apixaban content in the tablets was calculated according to the content uniformity test method of the 17th edition of the Japanese Pharmacopoeia. The results for the tablets of Example 2 are shown in Table 5.

[0074] [Table 5]

[0075] As shown in Table 5, the standard deviation of content uniformity at each tableting time was small at 0.17 for the tablets of Example 2. These results confirm that the apixaban-containing solid dosage form of this embodiment exhibits good content uniformity.

[0076] [Test Example 3] (Purity test) To evaluate the generation of related substances in the apixaban-containing solid dosage form of this embodiment, the following tests were performed in accordance with the apixaban tablet test method described in the United States Pharmacopeia (USP).

[0077] Preparation of standard solutions A standard solution was prepared by dissolving 1 μg of apixaban active pharmaceutical ingredient in a 1 / 1 mixed solution of acetonitrile / distilled water (by volume) for HPLC.

[0078] • Preparation of the measurement sample To obtain approximately 1000 μg of apixaban, granulated powder and tablets were placed in a 1 / 1 mixed solution of acetonitrile / distilled water for HPLC (by volume) and thoroughly dissolved. The resulting solution was filtered through a hydrophilic filter (0.45 μm) to prepare the sample for measurement.

[0079] Preparation of the mobile phase A 0.77 g / L ammonium acetate aqueous solution / acetonitrile = 2 / 8 aqueous solution (volume ratio) (mobile phase A) and acetonitrile (mobile phase B) were prepared. The gradient was analyzed according to the proportions shown in the table. A silica-supported reversed-phase chromatography column (C18, inner diameter 4.6 mm, column length 250 mm, pore size 5 μm) was used, and measurements were taken under the following conditions: detector 280 nm, column temperature 45 °C, liquid flow rate 1 mL / min, and injection volume 10 μL.

[0080] [Table 6]

[0081] As shown in Table 6, the content of the structurally unknown compound and apixaban-related substance in tablet 2 was lower than that of the apixaban raw material, and no generation or increase of apixaban-related substances or structurally unknown compounds was observed. These results confirm that the apixaban-containing solid dosage form of this embodiment suppresses the generation of apixaban-related substances.

Claims

1. This is an apixaban-containing composition that includes crystalline apixaban particles. The primary particles of the crystalline apixaban particles consist only of crystalline apixaban and a swelling agent. A apixaban-containing composition wherein the swelling agent is one or more selected from the group consisting of carmellose, crystalline cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose.

2. The apixaban-containing composition according to claim 1, wherein the content ratio (by mass) of crystalline apixaban to a swelling agent is 1:0.1 to 1:

10.

3. Furthermore, the apixaban-containing composition according to claim 1 further contains a surfactant.

4. A apixaban-containing composition according to any one of claims 1 to 3, which is in powder form.

5. A dispersion containing apixaban according to any one of claims 1 to 3.

6. A dispersion preparation step involves preparing a dispersion containing crystalline apixaban particles and a surfactant, After the dispersion preparation step, a granulation step is performed using the dispersion and excipient as raw materials. A formulation process is performed after the granulation process, in which a solid dosage form is manufactured using the obtained granules as a raw material. It has, At least a portion of the primary particles of the crystalline apixaban particles in the dispersion consist solely of crystalline apixaban and a swelling agent. A method for producing an apixaban-containing solid dosage form, wherein the swelling agent is one or more selected from the group consisting of carmellose, crystalline cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose.

7. The method for producing an apixaban-containing solid preparation according to claim 6, wherein the granulation is performed by a wet granulation method.

8. The method for producing an apixaban-containing solid preparation according to claim 6, wherein the content ratio (by mass) of crystalline apixaban to a swelling agent in the dispersion is 1:0.1 to 1:

10.

9. A method for producing an apixaban-containing solid preparation according to any one of claims 6 to 8, wherein the solid preparation is a tablet.

10. This is an apixaban-containing solid dosage form containing crystalline apixaban particles. The primary particles of the crystalline apixaban particles consist only of crystalline apixaban and a swelling agent. A solid preparation containing apixaban, wherein the swelling agent is one or more selected from the group consisting of carmellose, crystalline cellulose, sodium alginate, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropyl cellulose.

11. The apixaban-containing solid preparation according to claim 10, wherein the content ratio (by mass) of crystalline apixaban to swelling agent in the crystalline apixaban particles is 1:0.1 to 1:10.

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