Composition, pharmaceutical composition, solid preparation, and tablet

Abstract

To provide a composition that contains amorphous apixaban, enables size reduction during a preparation process, and exhibits superior dissolution from the preparation.SOLUTION: The present invention provides: a composition comprising apixaban, an amorphizing agent, and light anhydrous silicic acid, wherein the amorphizing agent is at least one selected from a hydrophilic nonionic polymer and a hydrophilic ionic polymer, and the apixaban is substantially free of crystalline apixaban; a pharmaceutical composition comprising the composition and a pharmaceutical additive; and a solid preparation containing the pharmaceutical composition.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a composition, a pharmaceutical composition, a solid preparation, and a tablet.

Background Art

[0002] Apixaban is sold under the name of Eliquis (registered trademark) tablets as a pharmaceutical for preventing blood coagulation. Apixaban is a poorly water-soluble drug and has poor absorbability from the digestive tract, so pharmaceutical ingenuity is required to enhance its absorbability.

[0003] To solve such problems, a solid dispersion having amorphous apixaban and a polymer for dispersing apixaban is known (see, for example, Patent Document 1). In the solid dispersion of Patent Document 1, by dispersing apixaban in a polymer, it becomes easier to maintain the amorphous state of apixaban. Therefore, the apixaban of Patent Document 1 is more easily dissolved in the body and absorbed from the digestive tract than crystalline apixaban.

[0004] However, in the solid dispersion of Patent Document 1, apixaban is dispersed in a large amount of polymer. Therefore, the preparation produced using the solid dispersion becomes large, and it tends to be difficult to take for elderly people and children who have difficulty swallowing.

[0005] On the other hand, an apixaban composition suitable for a miniaturized preparation is disclosed by reducing the amount of an amorphous agent (polymer) used (see, for example, Patent Document 2).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0007] Amorphous apixaban tends to crystallize and become less elutable when crystalline apixaban coexists. On the other hand, when an amorphizing agent (polymer) is used to maintain the amorphous state, the formulation tends to become larger and difficult to take. Generally, when the amount of the amorphizing agent used is reduced, the retention of the amorphous state becomes weak and crystallization becomes easy. Therefore, even in amorphous apixaban, there was a concern that crystallization would become easy and the elution amount would decrease.

[0008] Therefore, in a formulation containing apixaban, it is desired to make the formulation smaller and have higher elutability.

[0009] The present invention has been made in view of such circumstances, and an object thereof is to provide a composition and a pharmaceutical composition containing amorphous apixaban, which can be miniaturized during formulation and have excellent elutability from the formulation. Another object of the present invention is to provide a solid preparation and a tablet that are small and have excellent elutability and contain such a pharmaceutical composition.

Means for Solving the Problems

[0010] As a result of intensive studies to solve the problems, the present inventors have found that a formulation containing a composition containing amorphous apixaban, at least one of a hydrophilic nonionic polymer and a hydrophilic ionic polymer, and further containing light anhydrous silicic acid can be miniaturized and has excellent stability and elutability, and thus completed the present invention.

[0011] To solve the above problems, one aspect of the present invention includes the following aspects.

[0012] [1] A composition containing apixaban, an amorphizing agent, and light anhydrous silicic acid, wherein the amorphizing agent is at least one of a hydrophilic nonionic polymer and a hydrophilic ionic polymer, and the apixaban substantially does not contain crystalline apixaban.

[0013] [2] The composition according to [1], wherein the ratio of the amorphizing agent to apixaban is 5% by mass or more and less than 100% by mass.

[0014] [3] The composition according to [1], wherein the amorphizing agent is at least one selected from the group consisting of hypromellose acetate succinate, hypromellose phthalate, hypromellose, and hydroxypropyl cellulose.

[0015] [4] The composition according to [1], wherein apixaban and the amorphizing agent form a solid dispersion, and the composition is a mixture of the particles of the solid dispersion and the particles of the light anhydrous silicic acid.

[0016] [5] A pharmaceutical composition comprising the composition according to any one of [1] to [4] and a pharmaceutical additive.

[0017] [6] The pharmaceutical composition according to [5], wherein the pharmaceutical additive comprises at least one selected from the group consisting of crospovidone, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.

[0018] [7] A solid preparation containing the pharmaceutical composition according to [5].

[0019] [8] A tablet containing the pharmaceutical composition according to [5].

Advantages of the Invention

[0020] According to the present invention, there can be provided a composition and a pharmaceutical composition that contain amorphous apixaban, can be miniaturized during formulation, and have excellent elution properties from the formulation. Further, there can be provided a solid preparation and a tablet that are small in size and have excellent elution properties and contain such a pharmaceutical composition.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0022] 《Composition》 The composition of this embodiment contains apixaban, an amorphous agent, and light anhydrous silicic acid. As an example, the composition is a mixed powder of a powder of a solid dispersion containing apixaban and an amorphous agent and a powder of light anhydrous silicic acid. The following will be described in order.

[0023] [Solid dispersion] In this embodiment, "solid dispersion" means a solid in which at least a part of apixaban is dispersed at the molecular level in an amorphous agent. The solid dispersion contained in the composition of this embodiment is in powder form or particle form.

[0024] (Apixaban) The apixaban contained in the solid dispersion substantially does not contain crystalline apixaban, that is, substantially only amorphous apixaban is contained. "Substantially does not contain crystalline apixaban" means that when the composition of this embodiment or a single solid dispersion is measured by powder X-ray diffraction (XRD), in the obtained diffraction spectrum, a halo pattern corresponding to amorphous apixaban is predominantly detected and the peak of the crystal of apixaban is not detected.

[0025] In the composition of this embodiment, apixaban that substantially does not contain crystalline apixaban forms a solid dispersion with an amorphous agent. In the solid dispersion, amorphous apixaban is retained by the amorphous agent. Thereby, the apixaban contained in the solid dispersion has high stability.

[0026] That the "stability of apixaban is high" means (1) The amorphous apixaban contained in apixaban is likely to maintain an amorphous state (2) The decomposition and reaction of apixaban are suppressed It means

[0027] That the amorphous apixaban maintains the amorphous state means that the formation of apixaban crystals is suppressed under the conditions of 40 °C and 75% RH humidity with open air.

[0028] As a general quality of a pharmaceutical product, apixaban contained in the solid dispersion contains degradation products of apixaban and reaction products of apixaban (degradation products and reaction products are also referred to as related substances), with each related substance being 0.1% or less and the total related substances being 0.5% or less. Here, the related substances are known apixaban related substances such as oxides and reduction products of apixaban. The content rate of the related substances is the content rate determined by HPLC (HPLC content rate).

[0029] As the apixaban used as a raw material for preparing the solid dispersion, although it is not particularly limited, for example, those produced by known methods such as the methods described in International Publication No. WO2006 / 13545 and International Publication No. WO2007 / 001385 can be used.

[0030] Also, as the apixaban of the raw material, for example, apixaban with a particle size D 90 of 0.1 μm or more and 1000 μm or less can be used.

[0031] (Amorphizing agent) The amorphizing agent suppresses the crystallization of the amorphous apixaban contained in the solid dispersion. In the solid dispersion, it is considered that the crystallization of the amorphous apixaban is suppressed by the dispersion of the amorphous apixaban in the amorphizing agent.

[0032] The amorphizing agent contained in the composition of this embodiment is at least one of a hydrophilic nonionic polymer and a hydrophilic ionic polymer.

[0033] Examples of the hydrophilic ionic polymer include hypromellose acetate succinate, hypromellose phthalate, croscarmellose sodium, carrageenan, sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0034] Examples of the hydrophilic nonionic polymer include hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, ethyl cellulose, copovidone, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, polyethylene oxide, polypropylene glycol, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, carboxymethylethyl cellulose, dimethylaminoethyl ethyl methacrylate-methyl methacrylate copolymer, and methacrylic acid copolymer S.

[0035] As the amorphizing agent, one or more selected from the group consisting of hypromellose acetate succinate, hypromellose phthalate, hypromellose, and hydroxypropyl cellulose are preferable, one or more selected from the group consisting of hypromellose acetate succinate, hypromellose phthalate, and hypromellose are more preferable, and one or more selected from the group consisting of hypromellose acetate succinate and hypromellose phthalate are even more preferable.

[0036] In addition, the solid dispersion may contain the following pharmaceutical additives (excipients, lubricants, plasticizers, binders, disintegrants, fluidizing agents, surfactants, coloring agents, antistatic agents, etc.) as long as they do not affect the amorphization of apixaban.

[0037] In the solid dispersion, the ratio of the amorphous agent to apixaban is preferably 5% by mass or more and less than 100% by mass.

[0038] More preferably, the ratio is 8% by mass or more. Similarly, the ratio is preferably 10% by mass or more, 15% by mass or more, 20% by mass or more, 25% by mass or more, and 30% by mass or more, respectively.

[0039] Also, the ratio is preferably 80% by mass or less. Similarly, the ratio is preferably 75% by mass or less, 70% by mass or less, 65% by mass or less, 60% by mass or less, 55% by mass or less, and 50% by mass or less, respectively.

[0040] The upper limit and the lower limit of the above ratio can be arbitrarily combined. For example, the ratio of the amorphous agent to apixaban may be 30% by mass or more and less than 100% by mass, or may be 30% by mass or more and 70% by mass or less.

[0041] The average particle size of the solid dispersion is 1 to 100 μm, preferably 1 to 80 μm, and more preferably 2 to 60 μm. The average particle size is the median diameter (D 50 ) based on volume, and can be measured using a dry laser diffraction / scattering particle size distribution measuring device.

[0042] [Light anhydrous silicic acid] The composition of this embodiment contains powder (particles) of light anhydrous silicic acid together with the powder (particles) of the solid dispersion. Although the details are unknown, through the inventors' research, it has been found that a composition in which the solid dispersion and light anhydrous silicic acid coexist has excellent elution properties when formulated.

[0043] Light anhydrous silicic acid is a known compound described in the eighteenth revised Japanese Pharmacopoeia and is an inorganic porous substance. As light anhydrous silicic acid, for example, Aerosil manufactured by Nippon Aerosil Co., Ltd., Adsorider 101 manufactured by Freund Industry Co., Ltd., and Silicia manufactured by Fuji Silysia Chemical Ltd. can be used.

[0044] The content rate of light anhydrous silicic acid in the composition is preferably 10 parts by mass or more and 300 parts by mass or less with respect to 100 parts by mass of apixaban.

[0045] The content rate of light anhydrous silicic acid is preferably 10 parts by mass or more with respect to 100 parts by mass of apixaban. Similarly, the above content rate is preferably 20 parts by mass or more, 40 parts by mass or more, 50 parts by mass or more, 60 parts by mass or more, and 80 parts by mass or more, respectively.

[0046] Also, the content rate of light anhydrous silicic acid is preferably 300 parts by mass or less with respect to 100 parts by mass of apixaban. Similarly, the above content rate is preferably 250 parts by mass or less, 250 parts by mass or less, 200 parts by mass or less, 160 parts by mass or less, and 150 parts by mass or less, respectively.

[0047] The upper limit value and the lower limit value of the content rate of light anhydrous silicic acid can be arbitrarily combined. For example, the content rate of light anhydrous silicic acid in the composition may be 40% by mass or more and 200% by mass or less, or 80 parts by mass or more and 160 parts by mass or less with respect to 100 parts by mass of apixaban.

[0048] 《Method for manufacturing the composition》 The composition of this embodiment can be manufactured by mixing a solid dispersion and light anhydrous silicic acid after manufacturing the solid dispersion.

[0049] [Manufacturing of solid dispersion] The solid dispersion can be manufactured (granulated) by preparing a spray liquid of apixaban and an amorphizing agent, spraying the obtained spray liquid into an air stream (spray method), and removing the solvent from the droplets formed by spraying in a short time. Also, the spray liquid can be sprayed onto a flowing carrier and the solvent can be removed in a short time to manufacture (granulate).

[0050] When using a hydrophilic nonionic polymer or a hydrophilic ionic polymer as the amorphous agent, it is preferable to prepare a mixed solution of apixaban and the amorphous agent by the method of (1). For example, apixaban and the amorphous agent are dissolved in a solvent capable of dissolving them, and then a solid dispersion containing apixaban and the amorphous agent can be produced by a spraying method.

[0051] At this time, since the solvent is removed from the droplets formed by spraying in a short time, the apixaban contained in the obtained solid dispersion becomes amorphous. In addition, the amorphous agent contained in the solid dispersion retains the obtained amorphous apixaban and suppresses the crystallization of apixaban. Thereby, a solid dispersion containing amorphous apixaban and an amorphous agent can be suitably produced.

[0052] (Solvent) As the solvent in the solution of apixaban, any solvent can be used as long as apixaban is dissolved and it is used in pharmaceutical production. Such solvents include, for example, alcohols such as ethanol, methanol, 2-propanol; ketones such as acetone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran (THF), tetrahydropyran (THP), 1,4-dioxane, diethyl ether, diisopropyl ether, t-butyl methyl ether; aliphatic hydrocarbons such as hexane, heptane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO); aromatic hydrocarbons such as toluene; esters such as methyl acetate, ethyl acetate, butyl acetate; organic acids such as acetic acid, formic acid; water and the like. The solvent is selected according to the solubility of the amorphous agent to be used.

[0053] The above solvent may be used alone or in combination of two or more. When using a mixed solvent of two or more, examples of the combination of solvents include combinations of THF and water, THF and ethanol, acetone and water, ethanol and water, acetone and ethanol, and dichloromethane and ethanol.

[0054] Among the mixed solvents, a mixed solvent of dichloromethane and ethanol is preferred. When the total mass of dichloromethane and ethanol is set to 100, the mass ratio of dichloromethane:ethanol is preferably 95:5 to 5:95, more preferably 90:10 to 30:70, and even more preferably 90:10 to 50:50.

[0055] As the ethanol, for example, ethanol commonly used in the production of pharmaceuticals such as anhydrous ethanol and pharmacopoeial ethanol can be used, and anhydrous ethanol is preferably used.

[0056] The spray liquid only needs to have no undissolved residue and be at a concentration that can be sprayed. For example, the solid content is 0.1 to 80% by mass, preferably 1 to 70% by mass. Note that the "solid content" includes both apixaban and the amorphous agent.

[0057] (Spraying method) The obtained solution of apixaban is sprayed into an air stream to simultaneously remove the solvent and granulate.

[0058] Examples of the spraying method include the fluidized bed method, the spray drying method, the rolling fluidized bed method, etc. Since particles can be formed in a short time in an air stream and the elution property of the obtained particles is high, the spray drying method or the fluidized bed method is preferred.

[0059] The drying time by the spraying method is within 2 minutes, preferably within 1 minute, and more preferably within 30 seconds.

[0060] The above drying time is the time required to obtain a solid substance that has been solidified to the extent that the solvent is removed from the droplets sprayed with the apixaban solution and the shape can be maintained, and is not affected by the complete residual of the solvent. If the solvent residual rate of the obtained solid substance (solid dispersion) is 5% by mass or less, preferably 1% by mass or less, after drying by the above spraying method, apixaban contained in the solid substance can be obtained as an amorphous form.

[0061] If a problematic amount of solvent remains in the obtained solid substance for use as a pharmaceutical, it can be reduced to the residual solvent amount of the ICH guideline by a known method such as vacuum drying.

[0062] The spray drying method is carried out using a disk type or nozzle type (for example, pressure nozzle, two-fluid nozzle, four-fluid nozzle) spray dryer. As the temperature during spray drying, the inlet temperature is preferably about 30 to 100 °C, and the outlet temperature is preferably about 10 to 80 °C.

[0063] The solid dispersion may be supported by a carrier.

[0064] The solid dispersion supported by the carrier can be produced by spraying the above-mentioned spray liquid onto the carrier by a fluidized bed method, a spray drying method, a rolling layer method, etc. in the production of the solid dispersion.

[0065] The solid dispersion supported by the carrier can be produced using a nozzle type spray dryer. As the temperature conditions of the apparatus, the inlet temperature is preferably about 30 to 100 °C, and the outlet temperature is preferably about 10 to 80 °C. The air blowing conditions and the dynamic conditions of the carrier are arbitrarily set according to the apparatus used and the characteristics of the solvent and carrier used.

[0066] As the carrier, additives that can be used in pharmaceuticals can be used. Examples of the carrier include saccharides (such as glucose, fructose, lactose (including lactose hydrate), sucrose, trehalose, maltose, oligosaccharides, etc.), crystalline celluloses (such as crystalline cellulose), starches (such as corn starch, potato starch, rice starch, wheat starch, etc.), sugar alcohols (such as mannitol, erythritol, xylitol, sorbitol, maltitol, etc.), sodium phosphates, calcium phosphates (such as calcium hydrogen phosphate), gelatin, sucrose - starch spherical granules, lactose - crystalline cellulose spherical granules, spherical silicon dioxide, and the like.

[0067] In the case of the fluidized - bed method or the rolling - fluidized - bed method, a hydrophilic non - ionic polymer or a hydrophilic ionic polymer, which is an amorphous agent, is added to the solution of apixaban, and the obtained solution is sprayed onto the carrier, thereby obtaining a solid dispersion supported on the carrier. The hydrophilic non - ionic polymer and the hydrophilic ionic polymer also function as binders.

[0068] The solid dispersion obtained by the fluidized - bed method or the rolling - fluidized - bed method has a particle structure in which a drug layer containing amorphous apixaban and an amorphous agent is formed around the carrier.

[0069] The above - mentioned fluidized - bed method and rolling - fluidized - bed method can be carried out under the conditions usually used in the manufacture of pharmaceuticals. Also, after granulation, drying for removing the residual solvent can be appropriately carried out.

[0070] By mixing the particles of the solid dispersion obtained in this way with the particles of light anhydrous silicic acid, the composition of this embodiment is obtained.

[0071] 《Pharmaceutical Composition》 The pharmaceutical composition of this embodiment contains the above - mentioned composition and pharmaceutical additives.

[0072] Examples of the pharmaceutical additives include excipients, lubricants, plasticizers, binders, disintegrants, fluidizing agents, surfactants, light - shielding agents, pH adjusters, coloring agents, and antistatic agents. Specifically, they are as follows.

[0073] Excipients: For example, saccharides such as lactose, sucrose, trehalose, and glucose; sugar alcohols such as D-mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, and xylitol; crystalline cellulose, calcium hydrogen phosphate anhydrous, magnesium aluminometasilicate, etc. are mentioned. Preferably, lactose, sugar alcohol, or crystalline cellulose is mentioned.

[0074] Lubricants: For example, talc, glycerin monostearate, macrogol, magnesium stearate, calcium stearate, or sodium stearyl fumarate. Preferably, talc, glycerin monostearate, magnesium stearate, calcium stearate, or sodium stearyl fumarate. Most preferably, magnesium stearate is mentioned.

[0075] Plasticizers: 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, propylene glycol, glycerin, castor oil, polyoxyethylene hydrogenated castor oil, polysorbate 80, macrogol, lauromacrogol, triacetin, sorbitan monolaurate, monostearin, poloxamer, and polysorbate, etc. are mentioned. Preferably, triethyl citrate is mentioned.

[0076] Binders: For example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol, macrogol, pluronic F68, gum arabic, gelatin, starch, etc. are mentioned. Preferably, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose are mentioned. More preferably, hydroxypropyl methylcellulose, hydroxypropyl cellulose are mentioned.

[0077] Disintegrants: For example, starches such as corn starch and potato starch, pregelatinized starch, sodium carboxymethyl starch, carrageenan, carrageenan calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, etc.

[0078] Glidants: For example, talc, hydrated silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, etc.

[0079] Surfactants: For example, sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, and poloxamer, etc. Surfactants can be added to improve the dissolution rate of apixaban, especially to improve the dissolution rate up to about 10 minutes. The addition ratio (mass ratio) of the surfactant is 1:0.1 to 1:2 with respect to apixaban, preferably 1:0.2 to 1:1.

[0080] Sunblock agents: For example, titanium oxide, zinc oxide, talc, yellow iron oxide, iron oxide, black iron oxide, etc., and preferably titanium oxide.

[0081] Coating agents: For example, hypromellose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, and methacrylic acid copolymer, etc.

[0082] Colorants: For example, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible red No. 2, edible red No. 3, aluminum lake of edible blue No. 1, aluminum lake of edible blue No. 2, aluminum lake of edible red No. 2, iron oxide (red), titanium oxide, yellow iron oxide, caramel, talc, etc.

[0083] Antistatic agent: For example, silicon dioxide (including hydrated silicon dioxide), anhydrous silicon, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate, and glycerol monostearate.

[0084] The pharmaceutical additive may include one or more selected from the group consisting of lactose, crystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.

[0085] The pharmaceutical composition is obtained by mixing the above-described composition and the pharmaceutical additive.

[0086] The mixing can be carried out by generally used mixing methods, such as mixing, kneading, granulation, etc. The mixing can be carried out using, for example, a high-speed stirring mixer, a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, a double cone mixer, a ribbon-type mixer, a rotary screw-type mixer, manual mixing in a bag, etc.

[0087] 《Solid preparation, tablet》 The solid preparation and tablet of the present embodiment contain the above-described pharmaceutical composition.

[0088] When the solid preparation or tablet is an orally disintegrating tablet, in the above-described pharmaceutical composition, an excipient, a lubricant, a plasticizer, a binder, a disintegrant, a fluidizing agent, a surfactant, a coloring agent, an antistatic agent, etc. are mixed as pharmaceutical additives, and it is manufactured by compression molding with a tableting machine.

[0089] The obtained orally disintegrating tablet may be film-coated by a generally known method as necessary.

[0090] Compression molding can use a rotary tablet press or the like commonly used for pharmaceuticals. The molding pressure during tableting varies depending on the size of the tablet. For example, for a tablet with a diameter of 10 mm, it is 2 to 10 kN, preferably 3 to 9 kN, and for a tablet with a diameter of 8.5 mm, it is 2 to 6 kN, preferably 3 to 5 kN. At this time, the set hardness is 30 to 100 N, preferably 40 to 100 N, more preferably 50 to 90 N.

[0091] Since the obtained solid preparation and tablet contain the composition of this embodiment, they have excellent elution properties. The elution properties can be measured by the following method. (Measurement of elution properties) 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 properties are measured by the paddle method under the condition of 50 rpm, except that the method of the dissolution test in the Japanese Pharmacopoeia is used.

[0092] In the tablet evaluation in the examples described later, the elution property of apixaban in Comparative Example 1 is 40% in 10 minutes, while the elution property of apixaban in the tablet of Example 1 is 60% or more.

[0093] According to the composition having the above configuration, it contains amorphous apixaban, can be miniaturized during formulation, and is a composition and a pharmaceutical composition having excellent elution properties from the formulation.

[0094] Also, according to the solid preparation and tablet having the above configuration, by containing the above pharmaceutical composition, it is small and has excellent elution properties.

[0095] As described above, the preferred embodiments of the present invention have been described, but the present invention is not limited to such examples. The combinations and the like shown in the above examples are just examples, and various changes can be made based on the design, specifications, etc. without departing from the gist of the present invention.

Examples

[0096] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0097] (Reference Example 1) A spray solution was prepared by dissolving 50 g of crystalline apixaban and 10 g of hypromellose phthalate in a mixed solvent of 960 g of dichloromethane and 240 g of ethanol. From the obtained spray solution, using a spray dryer, a white powder with an average particle diameter (D 50 ) of 14 μm was obtained. The operating conditions of the apparatus were an air flow rate of 0.5 m 3 / min, an inlet heat of the spray solution of 70 °C, an exhaust heat of 40 °C, and a flow rate of 85 mL / min. The obtained powder was dried under reduced pressure at 40 °C overnight to obtain a powder of the solid dispersion.

[0098] Figure 1 is an XRD chart of the solid dispersion of Example 1. Figure 2 is an XRD chart of the crystalline apixaban used as a raw material. From the XRD results, it was confirmed that the solid dispersion had a dominant halo pattern corresponding to amorphous apixaban, and no peaks of the crystals of apixaban were detected, and it substantially did not contain crystalline apixaban.

[0099] (Reference Example 2) A powder of apixaban solid dispersion was obtained in the same manner as in Reference Example 1, except that a spray solution was prepared by dissolving 50 g of apixaban and 30 g of hypromellose phthalate in a mixed solvent of 1280 g of dichloromethane and 320 g of ethanol.

[0100] (Reference Example 3) A spray solution was prepared by dissolving 2.7 g of apixaban (particle size (D90) 136 μm) and 0.27 g of hypromellose phthalate as an amorphous agent in a mixed solvent of 48.45 g of dichloromethane and 8.55 g of ethanol.

[0101] From the obtained spray solution, using a spray dryer, a white powder was obtained. The operating conditions of the apparatus were an air flow rate of 0.5 m 3 / min, an inlet heat of the spray solution of 70 °C, an exhaust heat of 45 - 50 °C, and a flow rate of 6 - 7 g / min.

[0102] The obtained powder was dried under reduced pressure at 40 °C overnight to obtain a powder of the solid dispersion.

[0103] (Reference Example 4) to (Reference Example 7) A solid dispersion was produced in the same manner as in Reference Example 3, except that the amorphizing agent used was changed as shown in Table 1.

[0104]

Table 1

[0105] (Example 1) 6 parts by mass of the solid dispersion produced in Reference Example 1, 6 parts by mass of light anhydrous silicic acid, 2 parts by mass of sodium lauryl sulfate, 135 parts by mass of lactose, 40 parts by mass of crystalline cellulose, 7.5 parts by mass of croscarmellose sodium, and 3 parts by mass of magnesium stearate were mixed to prepare a pharmaceutical composition. Using a φ8×R12 punch, tableting was performed with a set hardness of 80 N to obtain 200 mg tablets containing 5 mg of apixaban.

[0106] (Example 2) Tablets were produced in the same manner as in Example 1, except that 8 parts by mass of the solid dispersion produced in Reference Example 2 and 133 parts by mass of lactose were used.

[0107] (Examples 3) to (Examples 7) The solid dispersion produced in Reference Example 3, light anhydrous silicic acid, and the pharmaceutical additives in Table 2 were mixed to prepare a pharmaceutical composition. Then, using a φ8×R12 punch, tableting was performed with a set hardness of 80 N to obtain the tablets of Example 3. In addition, the tablets of Examples 4 to 7 were obtained in the same manner as in Example 3, except that the solid dispersions produced in Reference Examples 4 to 7 were used. Each numerical value described in Table 2 represents parts by mass.

[0108]

Table 2

[0109] (Comparative Example 1) 6 parts by mass of the solid dispersion produced in Reference Example 1, 2 parts by mass of sodium lauryl sulfate, 141 parts by mass of lactose, 40 parts by mass of crystalline cellulose, 7.5 parts by mass of croscarmellose sodium, and 3 parts by mass of magnesium stearate were mixed to prepare a pharmaceutical composition. Using a φ8×R12 pestle, with a set hardness of 80 N, 200 mg tablets containing 5 mg of apixaban were obtained.

[0110] [Measurement of dissolution rate] 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, except that the condition was 50 rpm by the paddle method, the dissolution rate (%) of apixaban after 60 minutes was measured for the tablets of Example 1 and Comparative Example 1 according to the elution test method of the Japanese Pharmacopoeia. The measurement results are shown in Table 3.

[0111]

Table 3

[0112] The preparation of Example 1 showed a higher dissolution rate than Comparative Example 1 which did not contain light anhydrous silicic acid, indicating that it was a preparation with excellent dissolution properties.

[0113] From the above results, it was possible to miniaturize by reducing the content of the polymer which is an amorphous agent, and an apixaban preparation showing excellent dissolution behavior was obtained.

[0114] (Reference Example 8)~(Reference Example 23) A solid dispersion was produced in the same manner as Reference Example 3 except that the amorphous agent used was changed as shown in Table 4.

[0115]

Table 4

[0116] The numerical values in the table indicate the mass ratio of each component. Tablets can be produced in the same manner as Example 3 except that the solid dispersions of Reference Examples 8 to 23 are used respectively.

[0117] In addition to Table 4, when hypromellose acetate succinate, hypromellose phthalate or a mixture thereof is defined as "Group A", and hypromellose, hydroxypropyl cellulose or a mixture thereof is defined as "Group B", Group B can be used for Group A in a range of, for example, 1.0:0.05 to 10 by mass ratio. Group A and Group B can preferably be used in combination at a ratio of 1.0:0.07 to 8, more preferably 1.0:0.08 to 7, still more preferably 1.0:0.09 to 5, and even more preferably 1.0:0.1 to 3.

[0118] That is, when the mass of Group A is [A] and the mass of Group B is [B], the mass ratio of Group B to Group A ([B] / [A]) can be 0.05 ≤ [B] / [A] ≤ 10, preferably 0.07 ≤ [B] / [A] ≤ 8, more preferably 0.08 ≤ [B] / [A] ≤ 7, still more preferably 0.09 ≤ [B] / [A] ≤ 5, and even more preferably 0.1 ≤ [B] / [A] ≤ 3.

Claims

1. A pharmaceutical composition comprising apixaban, an amorphizing agent, and light anhydrous silicic acid, the amorphizing agent is at least one of a hydrophilic nonionic polymer and a hydrophilic ionic polymer; The composition is substantially free of crystalline apixaban.

2. The composition according to claim 1, wherein the ratio of the amorphous agent to the apixaban is 5% by mass or more and less than 100% by mass.

3. The composition according to claim 1, wherein the amorphous agent is one or more selected from the group consisting of hypromellose acetate succinate, hypromellose phthalate, hypromellose and hydroxypropyl cellulose.

4. the apixaban and the amorphizing agent form a solid dispersion; The composition according to claim 1 , wherein the composition is a mixture of particles of the solid dispersion and particles of the light anhydrous silicic acid.

5. A pharmaceutical composition comprising the composition according to any one of claims 1 to 4 and a pharmaceutical additive.

6. 6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical additive comprises one or more selected from the group consisting of crospovidone, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate.

7. A solid formulation comprising the pharmaceutical composition according to claim 5.

8. A tablet comprising the pharmaceutical composition according to claim 5.

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