Pharmaceutical composition containing eltrombopag or pharmaceutically acceptable salt thereof, method for producing the same, and method for suppressing dissolution delay

Abstract

To provide a pharmaceutical composition including eltrombopag or a pharmaceutically acceptable salt thereof, and a method for producing the composition, the composition exhibiting suppressed dissolution delay.SOLUTION: A pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof is characterized by setting the water content in the pharmaceutical composition to 3.5% or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for producing the same.The present invention relates to a method for suppressing delayed dissolution of a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Eltrombopag is a compound represented by the following structural formula, and its chemical name is 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid. Eltrombopag is a thrombopoietin receptor agonist and a compound that promotes platelet production and hematopoiesis.

[0003] [ka]

[0004] Patent Document 1 discloses tablets containing eltrombopag olamine, a bis(2-aminoethanol) salt of eltrombopag, as an active ingredient, and a method for producing the same. Patent Document 1 also describes that the dissolution properties of the active ingredient were confirmed for tablets produced using various formulations. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2010-526140 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have discovered a problem in stability tests of pharmaceutical compositions containing eltrombopag or a pharmaceutically acceptable salt thereof as an active ingredient, namely, a decrease in dissolution rate. An object of the present invention is to provide a pharmaceutical composition in which the dissolution delay of eltrombopag or a pharmaceutically acceptable salt thereof is suppressed, a method for producing the same, and a method for suppressing the dissolution delay of a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof. [Means for solving the problem]

[0007] The present inventors have discovered that in a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, delayed dissolution of eltrombopag or a pharmaceutically acceptable salt thereof can be suppressed by controlling the water content in the pharmaceutical composition, and have completed the present invention. Accordingly, the present invention provides a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, wherein the water content in the pharmaceutical composition is 3.5% or less.

[0008] The present invention provides a method for producing a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, the method comprising the step of drying a composition containing eltrombopag or a pharmaceutically acceptable salt thereof and water so that the water content in the composition is 3.5% or less to obtain a pharmaceutical composition.

[0009] The present invention provides a method for suppressing delayed dissolution of a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, by controlling the water content of the pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof to 3.5% or less. [Effects of the Invention]

[0010] According to the present invention, it is possible to provide a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, in which the dissolution delay is suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0011] The pharmaceutical composition of this embodiment is characterized in that it contains Eltrompovagus or a pharmaceutically acceptable salt thereof as an active ingredient, and the water content in the pharmaceutical composition is 3.5% or less.

[0012] The dosage form of the pharmaceutical composition of this embodiment is not particularly limited, but a preferred dosage form is a solid dosage form. Examples include tablets, capsules, powders, and granules. Among these, tablets are particularly preferred. The tablets may be plain or coated. Plain tablets are uncoated tablets and are also called bare tablets. Examples of coated tablets include film-coated (FC) tablets and sugar-coated tablets. Preferably, the pharmaceutical composition of this embodiment is a film-coated tablet. The coating agent described below can be used for film coating, and it is preferable to have a water-soluble film coating layer using a water-soluble polymer.

[0013] Pharmaceutically acceptable salts of eltrombopag include, for example, inorganic base salts and organic base salts of eltrombopag. Such salts include, for example, inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, aluminum salt, and zinc salt, and organic base salts such as trimethylamine, triethylamine, dimethylamine, diethylamine aniline, methylamine, ethylamine, pyridine, pyrrolidine, piperidine, morpholine, piperazine, bis(2-aminoethanol), cyclohexylamine, meglumine, and lysine. Preferably, the pharmaceutically acceptable salt of eltrombopag is eltrombopag olamine.

[0014] The content of eltrombopag or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of this embodiment is not particularly limited. When the pharmaceutical composition contains eltrombopag olamine, the content may be, for example, 15 mg to 128 mg (equivalent to 11.7 mg to 100 mg of eltrombopag mass). Here, this content refers to the mass of eltrombopag or a pharmaceutically acceptable salt thereof contained in a single dosage form of the pharmaceutical composition of this embodiment. As used herein, the term "single dosage form" refers to a unit amount corresponding to the dosage form of the pharmaceutical composition. When the pharmaceutical composition of this embodiment is in the form of granules or powder, a single dosage form is, for example, a single packet of a formulation in which a predetermined amount of granules or powder is individually packaged in a strip (SP) package, pillow package, or stick package. A predetermined amount of granules or powder is, for example, a mass of granules or powder that can be taken by an adult at one time. The granules or powder in one packet contain, for example, 15 mg to 128 mg of eltrombopag olamine (11.7 mg to 100 mg of eltrombopag). When the pharmaceutical composition of this embodiment in the form of granules or powder is packaged in a bottle, the bottle may contain more than one dosage form of granules or powder. In this case, one dosage form of the pharmaceutical composition of this embodiment can be obtained by taking a portion of the granules or powder contained in the bottle and weighing it. When the pharmaceutical composition of this embodiment is in the form of a tablet or capsule, one dosage form is one tablet or one capsule. In this case, one tablet or one capsule (hereinafter also referred to as "one capsule") contains, for example, 15 mg to 128 mg of eltrombopag olamine (11.7 mg to 100 mg of eltrombopag).

[0015] The content of eltrombopag olamine in the pharmaceutical composition of this embodiment can be, for example, 15.9 mg, 31.9 mg, 63.2 mg, 95.7 mg, or 128 mg (12.5 mg, 25 mg, 50 mg, 75 mg, or 100 mg of eltrombopag, respectively).

[0016] The water content in the pharmaceutical composition of this embodiment is preferably measured by the Karl Fischer method. The Karl Fischer method itself is known and is described, for example, in the 18th Edition of the Japanese Pharmacopoeia. The Karl Fischer method may be either volumetric titration or coulometric titration. A commercially available Karl Fischer reagent and a solvent for water measurement may be used to measure the water content. For example, the solvent for water measurement is placed in a titration bottle, the Karl Fischer reagent is added dropwise to anhydrous the titration bottle, a lightly crushed sample (pharmaceutical composition) is added to the titration bottle, and the sample's water content can be measured by titrating it with a Karl Fischer reagent whose titer has been previously standardized with purified water.

[0017] The water content value in a pharmaceutical composition measured by the Karl Fischer method is expressed as % by mass, with the mass of the pharmaceutical composition being 100%. That is, the water content in the pharmaceutical composition of this embodiment is 3.5% by mass or less, with the mass of the pharmaceutical composition being 100%. When the water content of multiple pharmaceutical compositions is measured, the water content in the pharmaceutical composition may be a statistically representative value such as the mean, median, or mode. The water content in the pharmaceutical composition may be determined, for example, by collecting a portion as a sample from each production lot of the pharmaceutical composition, measuring the water content, and determining the measured value as the water content of the pharmaceutical composition of that production lot.

[0018] The water content in the pharmaceutical composition of this embodiment is preferably less than 3.5%, and may be, for example, 3.4%, 3.3%, 3.2%, 3.1%, 3.0%, 2.9%, 2.8%, 2.7%, 2.6%, 2.5%, 2.4%, 2.3%, 2.2%, 2.1%, 2.0%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0%.

[0019] The pharmaceutical composition of this embodiment is produced by the pharmaceutical composition production method described below, and the moisture content of the pharmaceutical composition is adjusted to 3.5% or less by the drying process in this production method. The produced pharmaceutical composition of this embodiment preferably maintains the moisture content of the pharmaceutical composition at 3.5% or less. To maintain the moisture content of the pharmaceutical composition at 3.5% or less, for example, the pharmaceutical composition of this embodiment may be airtightly packaged. Airtight packaging itself is known and refers to packaging that can prevent the intrusion of water and water vapor from the outside. As used herein, the term "airtight packaging" encompasses "airtight containers" and "sealed containers" as defined in the General Provisions of the Japanese Pharmacopoeia, 18th Edition. Examples of airtight packaging include press-through packages (PTPs), SP packages, pillow packages, bottle packages, and stick packages. These packages may also be combined. For example, a pharmaceutical composition may be packaged in a press-through package (PTP), and the PTP-packaged pharmaceutical composition may then be packaged in a pillow package. A combination of press-through packages and pillow packages is suitable for pharmaceutical compositions in the form of tablets and capsules.

[0020] The material for the airtight packaging is not particularly limited as long as it is moisture-proof, and examples thereof include plastic, metal, glass, cellophane, etc. Examples of plastic include polypropylene, polyester, polychlorotrifluoroethylene, polyvinyl chloride, polyethylene terephthalate (PET), glycol-modified PET, nylon, polyethylene (low-density, medium-density, or high-density), ethylene-vinyl acetate copolymer, ionomer resin, ethylene-methacrylic acid copolymer, polyacrylonitrile, polyvinylidene chloride, ethylene-vinyl alcohol copolymer resin, cyclic polyolefin, polycarbonate, polystyrene, and rigid polyvinyl chloride. Examples of metal include aluminum foil. The airtight packaging may be a multilayer (laminate) formed by laminating two or more materials. Examples of multilayers include a laminate of a polyvinyl chloride layer and a polychlorotrifluoroethylene layer, a laminate of a cyclic polyolefin layer and a polypropylene layer, a laminate of a cyclic polyolefin layer, an aluminum layer, and a polypropylene layer, and a laminate of an aluminum layer and a polyethylene layer.

[0021] A press-through package (PTP) may be a package in which tablets or capsules are individually stored in a predetermined number of pockets formed in a plastic sheet, and the plastic sheet is then covered with aluminum foil or a plastic film. A double-sided aluminum press-through package (PTP) may be used, in which the sheet in which the pockets are formed contains aluminum foil. SP packages, pillow packages, and stick packages may be packages in which pharmaceutical compositions are individually packaged using a sheet containing plastic and / or aluminum foil.

[0022] The pharmaceutical composition of this embodiment may be packaged together with a desiccant. The desiccant may be appropriately selected from those commonly used in the fields of pharmaceuticals and foods. Examples of such desiccants include silica gel, silica alumina gel, zeolite, quicklime, bentonite clay, calcium chloride, magnesium chloride, and magnesium oxide. These desiccants may also be mixed with activated carbon.

[0023] The pharmaceutical composition of this embodiment may further contain an excipient. In this embodiment, an excipient is an additive that adds bulk to a low-content active ingredient (main drug) and is added to facilitate handling during manufacturing. An excipient is also called a bulking agent or diluent. Note that reducing sugars, which will be described later, can provide the functions of additives other than excipients. Examples of such functions include binders, stabilizers, disintegrants, and sweeteners.

[0024] Examples of excipients include reducing sugars, celluloses, starches, sugar alcohols, maltodextrin, and the like. A single excipient may be used, or two or more excipients may be used in combination. A reducing sugar is a sugar that has a free or hemiacetal-linked aldehyde or ketone group in the molecule and exhibits reducing properties. The type of reducing sugar is not particularly limited, but examples include lactose, maltose, glucose, arabinose, fructose, galactose, cellobiose, and the like. In this specification, the term "lactose" encompasses both lactose anhydrate and lactose hydrate. When distinguishing between the two, hereinafter, the terms "lactose anhydrate" and "lactose hydrate" are used. Lactose hydrate is also referred to as lactose monohydrate. A single reducing sugar may be used, or two or more may be used in combination. Lactose hydrate is particularly preferred as a reducing sugar. Examples of cellulose include crystalline cellulose and powdered cellulose. Examples of starches include starch, pregelatinized starch, corn starch, etc. Examples of sugar alcohols include mannitol, sorbitol, lactitol, xylitol, maltitol, etc. Preferred excipients other than reducing sugars include crystalline cellulose, mannitol, powdered cellulose, starch, pregelatinized starch, lactitol, sorbitol, and maltodextrin, with crystalline cellulose and mannitol being particularly preferred.

[0025] The pharmaceutical composition of this embodiment may further contain pharmaceutically acceptable additives in addition to the pharmaceutically acceptable excipient. Examples of such additives include binders, disintegrants, lubricants, coating agents, and colorants. The additives other than the excipients may be a single type or a combination of two or more types. The additives to be included can be appropriately determined, for example, depending on the dosage form of the pharmaceutical additive. Preferably, the pharmaceutical composition of this embodiment further contains a binder. More preferably, the pharmaceutical composition of this embodiment further contains a binder, a disintegrant, and a lubricant. Even more preferably, the pharmaceutical composition of this embodiment further contains a binder, a disintegrant, a lubricant, and a coating agent. Although a given additive incorporated into the pharmaceutical composition of this embodiment may provide one or more functions in the pharmaceutical composition, those skilled in the art will recognize that the purpose of incorporating the additive is to provide one primary function.

[0026] Examples of binders include vinyl polymers, celluloses, acrylic polymers, hydroxypropyl starch, dextrin, stearyl alcohol, gelatin, gum arabic, pullulan, and macrogol. A single binder may be used, or two or more binders may be used in combination. Examples of vinyl polymers include polyvinyl alcohol, polyvinylpyrrolidone (hereinafter also referred to as "povidone"), copolyvidone, and polyvinyl acetal diethylaminoacetate. Examples of celluloses include hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (also referred to as hypromellose), and ethyl cellulose. Examples of acrylic polymers include aminoalkyl methacrylate copolymers (E or RS), methacrylic acid copolymers (L, LD, or S), and ethyl acrylate-methyl methacrylate copolymer dispersions. Among these, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and ethyl cellulose are preferred, with polyvinyl alcohol and polyvinylpyrrolidone being particularly preferred.

[0027] In this specification, the term "polyvinyl alcohol" includes both fully saponified and partially saponified polyvinyl alcohol. When distinguishing between the two, they will be referred to as "polyvinyl alcohol (fully saponified)" and "polyvinyl alcohol (partially saponified)" below. When the degree of saponification of polyvinyl alcohol is less than 100 mol%, the structural formula of polyvinyl alcohol is -(CH2-CH(OH)-) n -(CH2-CH(OCOCH3)-) m The degree of saponification is the ratio (mol%) of hydroxyl groups to the total number of acetate groups and hydroxyl groups in polyvinyl alcohol. For example, the degree of saponification of polyvinyl alcohol with the above structural formula is calculated using the formula [n / (n+m)] x 100. Polyvinyl alcohol with a degree of saponification of 100 mol% is represented by -(CH2-CH(OH)-) n The degree of saponification of polyvinyl alcohol is not particularly limited. In general, the degree of saponification of polyvinyl alcohol (completely saponified product) is known to be 97 mol% or more, and the degree of saponification of polyvinyl alcohol (partially saponified product) is known to be 78 mol% or more and 96 mol% or less.

[0028] The degree of polymerization of polyvinyl alcohol is not particularly limited. Generally, the difference in the degree of polymerization of polyvinyl alcohol is often expressed by viscosity. The viscosity of polyvinyl alcohol is not particularly limited, but for example, if the viscosity (dynamic viscosity) of a 4% solution at 20°C is 2 mm 2 / s or more 100 mm 2 / s or less. The viscosity can be measured, for example, by the rotational viscometer method described in the Japanese Pharmacopoeia. Alternatively, the viscosity of polyvinyl alcohol may be a value disclosed by the manufacturer or distributor.

[0029] The K value of polyvinylpyrrolidone is not particularly limited, but is, for example, from 10 to 120, preferably from 30 to 90. The K value is a viscosity characteristic value that correlates with molecular weight. Measurement and calculation of the K value of polyvinylpyrrolidone are known per se, and can be calculated, for example, by applying the relative viscosity value (25°C) of a polyvinylpyrrolidone solution measured with a capillary viscometer to the Fikentscher equation. Alternatively, the K value of polyvinylpyrrolidone may be a value disclosed by the manufacturer or distributor.

[0030] Examples of disintegrants include sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose, carmellose sodium, carmellose calcium, and low-substituted hydroxypropyl cellulose. Among these, sodium starch glycolate, crospovidone, and croscarmellose sodium are preferred, and sodium starch glycolate is particularly preferred. The disintegrants may be used alone or in combination of two or more.

[0031] The content of the disintegrant in the pharmaceutical composition of this embodiment is not particularly limited, but may be, for example, 4% by mass to 10% by mass relative to the mass of the pharmaceutical composition. The content of the disintegrant relative to the mass of the pharmaceutical composition is preferably 5% by mass to 9% by mass, and more preferably 6% by mass to 8% by mass.

[0032] Examples of lubricants include magnesium stearate, calcium stearate, talc, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, liquid paraffin, sodium oleate, light anhydrous silicic acid, and hydrogenated vegetable oil. Among these, magnesium stearate, calcium stearate, talc, stearic acid, and sodium stearyl fumarate are preferred, and magnesium stearate is particularly preferred. One type of lubricant may be used, or two or more types may be combined.

[0033] The content of the lubricant in the pharmaceutical composition of this embodiment is not particularly limited, but may be, for example, 0.7% by mass or more and 2% by mass or less, preferably 0.8% by mass or more and 1.5% by mass or less, and more preferably 0.9% by mass or more and 1% by mass or less, relative to the mass of the pharmaceutical composition.

[0034] Examples of coating agents include water-soluble polymers, water-insoluble polymers, gastrosoluble polymers, enteric polymers, and water-insoluble non-polymers. A single coating agent may be used, or two or more may be used in combination. Examples of water-soluble polymers include hypromellose, hydroxypropyl cellulose, the macrogol (also known as polyethylene glycol) series (e.g., Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macrogol 6000, Macrogol 20000, etc.), polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate), polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, triethyl citrate, and triacetin. Hydroxypropyl methylcellulose is commercially available under the trade name "TC-5®," with TC-5® E and TC-5® R being preferred, and TC-5® E being more preferred. Examples of water-insoluble polymers include ethyl cellulose, methacrylic acid copolymers, copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate, methyl cellulose, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers. Examples of gastric-soluble polymers include aminoalkyl methacrylate copolymers and polyvinyl alcohol diethylaminoacetate. Examples of enteric polymers include methacrylic acid copolymers, cellulose acetate phthalate, hypromellose phthalate, and polyvinyl alcohol acetate phthalate. Examples of water-insoluble non-polymers include titanium oxide, talc, and light anhydrous silicic acid. Commercially available coating compositions, such as the OPADRY® and OPADRY® II series, may also be used as coating agents.

[0035] The content of the coating agent in the pharmaceutical composition of the present embodiment is not particularly limited, but may be, for example, 2% by mass or more and 6% by mass or less, preferably 2.5% by mass or more and 5.5% by mass or less, and more preferably 2.5% by mass or more and 5% by mass or less, relative to the mass of the pharmaceutical composition.

[0036] Examples of colorants include ferric oxide, yellow ferric oxide, titanium oxide, Yellow No. 4 Aluminum Lake, and Yellow No. 5 Aluminum Lake. A single colorant may be used, or two or more may be used in combination. The colorant is preferably contained in the coating of a film-coated tablet. The content of the colorant in the pharmaceutical composition of this embodiment is not particularly limited, and may be, for example, 0.05% by mass or more and 0.5% by mass or less, preferably 0.1% by mass or more and 0.4% by mass or less, and more preferably 0.15% by mass or more and 0.3% by mass or less, relative to the total mass of the coating agent.

[0037] It is known that when a coordination metal comes into contact with eltrombopag or a pharmaceutically acceptable salt thereof, it forms an insoluble metal complex, which can slow the dissolution of eltrombopag or a pharmaceutically acceptable salt thereof from the pharmaceutical composition. Therefore, the pharmaceutical composition of this embodiment is preferably substantially free of a coordination metal. More specifically, the pharmaceutical composition of this embodiment does not contain a coordination metal, or, if it contains a coordination metal, the content of the coordination metal is 3% by mass or less relative to the content of eltrombopag or a pharmaceutically acceptable salt thereof. A coordination metal is a metal that can form a metal complex. A coordination metal can also be contained in a pharmaceutically acceptable additive. Examples of coordination metals include aluminum, calcium, copper, cobalt, gold, iron, magnesium, manganese, and zinc.

[0038] It is known that when eltrombopag olamine comes into contact with a reducing sugar, the Maillard reaction occurs, resulting in decomposition of eltrombopag olamine and the production of related substances. When the pharmaceutical composition of this embodiment contains a reducing sugar as an excipient, the pharmaceutical composition of this embodiment preferably has at least one characteristic selected from the following, in order to suppress the production of related substances. (i) The content of eltrombopag olamine relative to the mass of the pharmaceutical composition is 8% by mass or more and 30% by mass or less; and (ii) Contains polyvinyl alcohol as a binder.

[0039] When the pharmaceutical composition of this embodiment contains a reducing sugar as an excipient and polyvinyl alcohol as a binder, the content of eltrombopag olamine relative to the mass of the pharmaceutical composition of this embodiment can be 8% by mass or more and 20% by mass or less.

[0040] When a reducing sugar is contained as an excipient, the content of the reducing sugar in the pharmaceutical composition of this embodiment is preferably greater than 5% by mass and less than 35% by mass, based on the total mass of the excipient including the reducing sugar. For example, the content of the reducing sugar is greater than 5% by mass and less than 10% by mass, or 6.5% by mass to 9.5% by mass, or 7% by mass to 9% by mass, based on the total mass of the excipient including the reducing sugar. Here, the total mass of the excipient including the reducing sugar is the sum of the mass of the reducing sugar and the mass of the excipient other than the reducing sugar contained in a single dosage form of the pharmaceutical composition of this embodiment.

[0041] The pharmaceutical composition of this embodiment can be produced by a production method comprising drying a composition containing eltrombopag or a pharmaceutically acceptable salt thereof and water to obtain a pharmaceutical composition with a water content of 3.5% or less. In this embodiment, the water contained in the composition includes both water contained throughout the composition and water contained locally in a portion of the composition (e.g., the surface). An example of a composition in which water is contained throughout the composition is a granulated product obtained by wet granulation before drying. An example of a composition in which water is contained locally in a portion of the composition is an FC tablet after spraying with a coating liquid and before drying. In the production method of this embodiment, the pharmaceutical composition of this embodiment can be obtained by drying the composition to obtain a water content of 3.5% or less.

[0042] The form of eltrombopag or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is solid, and may be in any form, such as powder or particles. Preferably, powder of eltrombopag or a pharmaceutically acceptable salt thereof is used. Details of the excipients are as described above. In a preferred embodiment, mannitol and crystalline cellulose are used as excipients.

[0043] The method for mixing eltrombopag or a pharmaceutically acceptable salt thereof with an excipient is not particularly limited. For example, when a mixed powder containing eltrombopag or a pharmaceutically acceptable salt thereof and an excipient powder is to be obtained, a known mixer capable of mixing two or more types of powders may be used. Examples of such mixers include a diffusion mixer and a convection mixer. Furthermore, when a granular composition containing a mixture of eltrombopag or a pharmaceutically acceptable salt thereof and an excipient containing a reducing sugar is to be obtained, a known granulator capable of mixing two or more types of powders may be used. Examples of such granulators include a dry granulator, an extrusion granulator, a stirring mixer granulator, and a fluidized bed granulator dryer.

[0044] When the pharmaceutical composition of this embodiment is a powder, the mixed powder containing eltrombopag or a pharmaceutically acceptable salt thereof produced by the above-described mixing can be obtained as a powder containing eltrombopag or a pharmaceutically acceptable salt thereof. The content of eltrombopag olamine in the powder per dosage form can be, for example, 15 mg to 128 mg (11.7 mg to 100 mg of eltrombopag). The amount of each component in the powder per dosage form can be scaled up depending on the amount of powder to be produced. The details of the content of eltrombopag or a pharmaceutically acceptable salt thereof relative to the mass of the powder per dosage form are as described for the pharmaceutical composition of this embodiment.

[0045] In a preferred embodiment, a granular composition containing eltrombopag or a pharmaceutically acceptable salt thereof, an excipient, and a binder is prepared by a known granulation method. In this case, the resulting granular composition can be used as a granulated pharmaceutical composition. The granulation method may be either wet granulation or dry granulation, with wet granulation being preferred. In wet granulation, a granular composition is prepared by using a mixture of eltrombopag or a pharmaceutically acceptable salt thereof and an excipient, and a solution or suspension containing a binder. If necessary, a powdered binder and / or disintegrant may be further added to the mixture before wet granulation. Alternatively, a granular composition may be prepared by mixing eltrombopag or a pharmaceutically acceptable salt thereof, an excipient, and a binder and / or disintegrant, and then wet granulating the resulting mixture with a solution or suspension containing a binder. Details of the binder and disintegrant are as described above. The binder is preferably polyvinyl alcohol or polyvinylpyrrolidone, and the disintegrant is preferably sodium starch glycolate.

[0046] The above-mentioned solution or suspension containing a binder is a granulation liquid used in wet granulation. The granulation liquid can be prepared by dissolving or dispersing a binder in a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include purified water, ethanol, and mixtures thereof. Among these, purified water is particularly preferred.

[0047] The type of wet granulation is not particularly limited, and can be appropriately selected from, for example, agitation granulation, fluidized bed granulation, extrusion granulation, tumbling granulation, crushing granulation, spray granulation, etc. Wet granulation can be carried out using a known granulator. For example, when using an agitation mixer granulator, the mixed powder is agitated with a rotating blade, and a solution or suspension containing a binder is added dropwise or sprayed thereto, whereby the mixed powder and the solution or suspension containing a binder are mixed and dispersed to produce a granular composition containing eltrombopag or a pharmaceutically acceptable salt thereof.

[0048] The granular composition obtained by wet granulation is dried to a moisture content of 3.5% or less. This allows the pharmaceutical composition of this embodiment in granular form to be obtained. The drying method is not particularly limited and can be appropriately selected from, for example, vacuum drying, fluidized bed drying, spray drying, etc. If the granulator is equipped with a drying function (e.g., a fluidized bed granulation dryer), the granulation may be performed using the granulator. In this embodiment, the moisture content of the granular composition after drying may be measured to confirm that it is 3.5% or less. For example, a portion of the granular composition after drying is sampled and the moisture content is measured by the Karl Fischer method. The moisture content measurement is as described above. If the moisture content is higher than 3.5%, the granular composition is further dried. If the drying conditions are established such that the moisture content of the granular composition is 3.5% or less, the moisture content measurement may be omitted. Drying conditions include, for example, the preheating of the apparatus, the intake air temperature, the intake air volume, and the drying time. A person skilled in the art of pharmaceutical manufacturing can empirically determine the drying conditions for achieving a moisture content of 3.5% or less of the composition without excessive trial and error. In this embodiment, the dried granular composition may be sized using a known sizing machine so that the dried granular composition has a predetermined particle size distribution.

[0049] The powder pharmaceutical composition or granule pharmaceutical composition obtained as described above can be filled into capsules to produce a capsule pharmaceutical composition. In the capsule pharmaceutical composition, the powder or granules can be filled in an amount such that the content of eltrombopag or a pharmaceutically acceptable salt thereof per capsule is, for example, 15 mg to 128 mg in the case of eltrombopag olamine.

[0050] The capsules are not particularly limited as long as they are hard capsules made from a pharmaceutically acceptable capsule base such as gelatin, hydroxypropylmethylcellulose, etc. The method of filling powder into capsules is known per se, and for example, any of the disc, compress, and Auger type filling machines can be used.

[0051] The granular composition containing eltrombopag or a pharmaceutically acceptable salt thereof obtained as described above can be used as a tableting mixture for producing the pharmaceutical composition of this embodiment in the form of a tablet. In a further embodiment of the present invention, a method for producing tablets containing eltrombopag or a pharmaceutically acceptable salt thereof as an active ingredient (hereinafter also referred to as a "tablet production method") is provided. The tablet production method of this embodiment includes the steps of: mixing eltrombopag or a pharmaceutically acceptable salt thereof with an excipient containing a reducing sugar; wet granulating the mixture obtained in this mixing step with a solution or suspension containing a binder to obtain a granular composition containing eltrombopag or a pharmaceutically acceptable salt thereof and water; and drying the granular composition. Details of these steps are as described above. When obtaining uncoated tablets as the pharmaceutical composition of this embodiment, the granular composition is dried so that the water content in the composition is 3.5% or less in the drying step. When obtaining FC tablets as the pharmaceutical composition of this embodiment, the water content in the granular composition in the drying step may be higher than 3.5%. In this case, the uncoated tablets are dried after film coating so that the moisture content in the tablets is 3.5% or less.

[0052] In the tablet manufacturing method of this embodiment, the granular composition containing eltrombopag or a pharmaceutically acceptable salt thereof is mixed with tablet additives to obtain a tableting mixture. For example, when the granular composition contains eltrombopag olamine, the mixing is performed so that the content of eltrombopag olamine per tablet is 8% by mass or more and 30% by mass or less. Furthermore, when the granular composition contains polyvinyl alcohol as a binder, the mixing may be performed so that the content of eltrombopag olamine per tablet is 8% by mass or more and 20% by mass or less. The details of the ratio of the content of eltrombopag or a pharmaceutically acceptable salt thereof to the mass of the pharmaceutical composition are as described for the pharmaceutical composition of this embodiment.

[0053] Tablet additives are pharmaceutically acceptable additives commonly used in tablet production. Tablet additives can be appropriately selected from, for example, excipients, binders, disintegrants, lubricants, sweeteners, colorants, etc. Details of these additives are as described above. As tablet additives, excipients, disintegrants, and lubricants are preferably used. As excipients, crystalline cellulose and mannitol are preferred. As disintegrants, sodium starch glycolate is preferred. As lubricants, magnesium stearate is preferred.

[0054] Preferably, in mixing a granular composition containing eltrombopag or a pharmaceutically acceptable salt thereof with tablet additives containing a disintegrant, the granular composition is first mixed with tablet additives excluding lubricants (e.g., excipients and disintegrants), and then the lubricant is added to the resulting mixture and mixed to obtain a mixture for tableting.

[0055] In the tablet manufacturing method of this embodiment, the obtained tableting mixture is compression-molded to obtain tablets containing eltrombopag or a pharmaceutically acceptable salt thereof as an active ingredient. The tableting mixture can be compression-molded using a known tablet press (e.g., a rotary tablet press). If necessary, the obtained tablets may be made into film-coated tablets or sugar-coated tablets. Preferably, the tablet manufacturing method of this embodiment further includes a step of film-coating the tablets. Tablet coating can be performed by known methods such as pan coating and fluidized bed coating. The coating agent used for film coating is as described above.

[0056] The process of film-coating tablets includes at least a process of coating plain tablets with a coating solution and a process of drying the coated tablets. In the tablet manufacturing method of this embodiment, in the process of drying the coated tablets (hereinafter also referred to as the "drying process"), the moisture content of the tablets may be measured to confirm that it is 3.5% or less. For example, in the drying process, one or more tablets are sampled every predetermined time, and the moisture content of the tablets is measured by the Karl Fischer method. The moisture content measurement is as described above. If the moisture content is higher than 3.5%, the tablets are further dried. If drying treatment conditions are established that result in a moisture content of 3.5% or less in the tablets after film coating, the measurement of the moisture content may be omitted.

[0057] In a further embodiment of the present invention, there is provided a method for suppressing delayed dissolution of a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof (hereinafter also referred to as a "method for suppressing delayed dissolution"). This method comprises controlling the water content of a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof to 3.5% or less. As used herein, "controlling the water content of a pharmaceutical composition to 3.5% or less" encompasses both drying a composition containing eltrombopag or a pharmaceutically acceptable salt thereof and water to 3.5% or less to obtain the pharmaceutical composition of this embodiment, and maintaining the water content of the resulting pharmaceutical composition of this embodiment at 3.5%. Drying the composition and maintaining the water content are as described above.

[0058] Another embodiment of the present invention relates to a pharmaceutical composition containing eltrombopag olamine as an active ingredient, comprising eltrombopag olamine and an excipient containing a reducing sugar, wherein the content of the eltrombopag olamine in the pharmaceutical composition is 8% to 30% by mass, the content of the reducing sugar in the pharmaceutical composition is 17.5% to 120% by mass, and the water content in the pharmaceutical composition is 3.5% or less. In this pharmaceutical composition, the content of eltrombopag olamine may be, for example, 15 mg to 128 mg. When the pharmaceutical composition of this embodiment contains polyvinyl alcohol as a binder, the content of eltrombopag olamine in the pharmaceutical composition may be 8% to 20% by mass. Furthermore, when the pharmaceutical composition of this embodiment contains polyvinyl alcohol as a binder, the content of the reducing sugar can be 35% by mass or more and 80% by mass or less, preferably 40% by mass or more and 70% by mass or less, relative to the content of eltrombopag olamine.

[0059] Another embodiment of the present invention relates to a method for producing a pharmaceutical composition containing eltrombopag olamine as an active ingredient, comprising the steps of mixing eltrombopag olamine with an excipient containing a reducing sugar and drying the resulting composition to a water content of 3.5% or less, thereby obtaining a pharmaceutical composition containing eltrombopag olamine, wherein the eltrombopag olamine content is 8% to 30% by mass, based on the mass of the pharmaceutical composition in a single dosage form, the reducing sugar content in the pharmaceutical composition in a single dosage form is 17.5% to 120% by mass, based on the mass of the eltrombopag olamine, and the water content in the pharmaceutical composition is 3.5% or less. In this production method, the eltrombopag olamine content in the pharmaceutical composition in a single dosage form may be, for example, 15 mg to 128 mg. When polyvinyl alcohol is added as a binder, the eltrombopag olamine content may be 8% to 20% by mass, based on the mass of the pharmaceutical composition. When polyvinyl alcohol is added as a binder, the content of the reducing sugar may be 35% by mass or more and 80% by mass or less, preferably 40% by mass or more and 70% by mass or less, relative to the content of eltrombopag olamine.

[0060] Another embodiment of the present invention relates to a method for producing tablets containing eltrombopag olamine as an active ingredient, the method comprising the steps of: mixing eltrombopag olamine with an excipient containing a reducing sugar; obtaining a granular composition by wet granulation using the mixture obtained in the mixing step and a solution or suspension containing a binder; drying the granular composition so that the water content in the granular composition is 3.5% or less; mixing the granular composition with a tablet additive containing a disintegrant to obtain a tableting mixture; and adding a lubricant to the tableting mixture and compressing the mixture to obtain tablets. The method relates to a method for producing tablets containing eltrombopag olamine as an active ingredient, the content of the eltrombopag olamine being 8% by mass or more and 30% by mass or less relative to the mass of the tablet, the content of the reducing sugar in each tablet being 17.5% by mass or more and 120% by mass or less relative to the mass of the eltrombopag olamine, and the water content in the tablet being 3.5% or less. In this manufacturing method, the content of eltrombopag olamine in one tablet may be, for example, from 15 mg to 128 mg. When polyvinyl alcohol is added as a binder, the content of eltrombopag olamine may be from 8% by mass to 20% by mass of the pharmaceutical composition. Furthermore, when polyvinyl alcohol is added as a binder, the content of reducing sugar may be from 35% by mass to 80% by mass, preferably from 40% by mass to 70% by mass of the eltrombopag olamine content.

[0061] Another embodiment of the present invention relates to a method for suppressing delayed dissolution of a pharmaceutical composition containing eltrombopag olamine as an active ingredient, comprising the steps of mixing eltrombopag olamine with an excipient containing a reducing sugar and drying the resulting composition to a water content of 3.5% or less, to produce a pharmaceutical composition containing eltrombopag olamine, wherein the content of the eltrombopag olamine in the pharmaceutical composition in a single dosage form is 8% by mass or more and 30% by mass or less, relative to the mass of the pharmaceutical composition, the content of the reducing sugar in the pharmaceutical composition in a single dosage form is 17.5% by mass or more and 120% by mass or less, relative to the mass of the eltrombopag olamine, and the water content in the pharmaceutical composition is 3.5% or less. When polyvinyl alcohol is added as a binder, the content of eltrombopag olamine in the pharmaceutical composition may be 8% by mass or more and 20% by mass or less. When polyvinyl alcohol is added as a binder, the content of the reducing sugar may be 35% by mass or more and 80% by mass or less, preferably 40% by mass or more and 70% by mass or less, relative to the content of eltrombopag olamine.

[0062] Yet another embodiment of the present invention relates to a pharmaceutical composition containing eltrombopag olamine as an active ingredient, the pharmaceutical composition comprising eltrombopag olamine, an excipient containing a reducing sugar, and polyvinyl alcohol, wherein the content of the reducing sugar in the pharmaceutical composition is 17.5% by mass to 120% by mass, both inclusive, relative to the content of the eltrombopag olamine, and the water content in the pharmaceutical composition is 3.5% or less. In this pharmaceutical composition, the content of eltrombopag olamine can be, for example, 15 mg to 128 mg.

[0063] Yet another embodiment of the present invention relates to a method for producing a pharmaceutical composition containing eltrombopag olamine as an active ingredient, comprising the steps of mixing eltrombopag olamine, an excipient containing a reducing sugar, and polyvinyl alcohol, and drying the resulting composition to a water content of 3.5% or less, to obtain a pharmaceutical composition containing eltrombopag olamine, wherein the content of the reducing sugar in a single dosage form of the pharmaceutical composition is 17.5% by mass to 120% by mass, relative to the content of eltrombopag olamine, and the water content in the pharmaceutical composition is 3.5% or less. In this production method, the content of eltrombopag olamine in a single dosage form of the pharmaceutical composition can be, for example, 15 mg to 128 mg.

[0064] Yet another embodiment of the present invention relates to a method for producing tablets containing eltrombopag olamine as an active ingredient, the method comprising the steps of: mixing eltrombopag olamine with an excipient containing a reducing sugar; wet granulating the mixture obtained in the mixing step with a solution or suspension containing polyvinyl alcohol to obtain a granular composition; drying the granular composition to a water content of 3.5% or less; mixing the granular composition with a tablet additive containing a disintegrant to obtain a tableting mixture; and adding a lubricant to the tableting mixture and compressing the mixture to obtain tablets. In this method, the content of the reducing sugar in each tablet is 17.5% to 120% by mass relative to the content of eltrombopag olamine, and the water content in each tablet is 3.5% or less. In this method, the content of eltrombopag olamine in each tablet can be, for example, 15 mg to 128 mg.

[0065] Yet another embodiment of the present invention relates to a method for suppressing delayed dissolution of a pharmaceutical composition containing eltrombopag olamine as an active ingredient, comprising the steps of mixing eltrombopag olamine, an excipient containing a reducing sugar, and polyvinyl alcohol, and drying the resulting composition so that the water content in the composition is 3.5% or less, to produce a pharmaceutical composition containing eltrombopag olamine, wherein the content of the reducing sugar in a single dosage form of the pharmaceutical composition is 17.5% by mass or more and 120% by mass or less relative to the content of eltrombopag olamine, and the water content in the pharmaceutical composition is 3.5% or less.

[0066] The pharmaceutical composition of this embodiment containing polyvinyl alcohol exhibits the additional effect of reducing the increase in related substances even when the content of reducing sugars is higher than that of pharmaceutical compositions not containing polyvinyl alcohol. In the pharmaceutical composition of this embodiment containing polyvinyl alcohol, the lower limit of the content of reducing sugars may be, for example, 35%, 36%, 37%, 38%, 39%, 40%, 45%, or 50% by mass relative to the content of eltrombopag olamine. The upper limit of the content of reducing sugars may be, for example, 120%, 115%, 110%, 105%, 100%, 95%, 90%, 80%, 75%, 70%, 65%, 60%, or 55% by mass relative to the content of eltrombopag olamine. For example, the content of reducing sugars may be greater than 35% by mass and less than 120% by mass, or greater than 40% by mass and less than 120% by mass, relative to the content of eltrombopag olamine. Preferably, the content of reducing sugars is greater than 35% by mass and less than 80% by mass, greater than 35% by mass and less than 70% by mass, greater than 40% by mass and less than 80% by mass, or greater than 40% by mass and less than 70% by mass, relative to the content of eltrombopag olamine.

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. [Example]

[0068] Film-coated (FC) tablets containing the same amount of eltrombopag olamine were manufactured in Manufacturing Examples 1 to 6 using the formulations (Formulation Examples 1 to 5) shown in Table 1. The formulations of the FC tablets in Manufacturing Examples 1 and 2 were both Formulation Example 1. The formulations of the FC tablets in Manufacturing Examples 3 to 6 were Formulation Examples 2 to 5, respectively. For each FC tablet, the moisture content of the tablet immediately after manufacturing and the difference in dissolution rate between immediately after manufacturing and after 2 weeks of storage at 50°C in a stability test were compared. The formulations shown in Table 1 indicate the amount of ingredients per tablet. In Table 1, the unit of the numerical values ​​for each ingredient is all "mg."

[0069] [Table 1]

[0070] 1. Manufacturing of FC tablets (1.1) Production of FC tablets of Production Example 1 The FC tablets of Production Example 1 were produced using a general FC tablet production method. Specifically, the process was as follows: Eltrombopag olamine powder, crystalline cellulose, D-mannitol, lactose hydrate, and polyvinyl alcohol (partially saponified) were mixed in a stirring mixer granulator to obtain a mixed powder. Polyvinyl alcohol (partially saponified) was dissolved in purified water to obtain a granulating liquid. The granulating liquid was sprayed onto the mixed powder in the stirring mixer granulator to granulate, obtaining a granulated product. The granulated product was crushed in a granulator and dried in a fluidized bed granulation dryer. The crushed and dried granulated product was sized in a granulator to obtain a granular composition containing eltrombopag olamine. The obtained granular composition, crystalline cellulose, and sodium starch glycolate were mixed in a tumbler mixer to obtain a mixed powder. A portion of this mixed powder was taken and mixed with magnesium stearate to obtain a triturated powder. This triturated powder and the remaining mixed powder were mixed in a tumbler mixer to obtain a mixture for tableting. The resulting tableting mixture was compressed using a rotary tablet press to obtain uncoated tablets containing eltrombopag olamine. Hypromellose (TC-5® R) and titanium oxide were added to and dispersed in a mixture of macrogol 400 and polysorbate 80 to obtain a coating solution. Uncoated tablets containing eltrombopag olamine were coated with the coating solution using a pan coating device, and the coated tablets were dried to obtain the FC tablets of Preparation Example 1. After the start of coating, portions of the tablets were sampled and their masses were measured at predetermined intervals to evaluate whether the coating was performed properly. After drying, the FC tablets were removed from the pan coating device, and their temperature was measured using a non-contact thermometer (PT-7LD, Optex FA). The temperature of the FC tablets at the end of drying was 43°C. After measuring the temperature, the FC tablets were stored in an airtight metal container until used in the moisture content measurement and dissolution test described below. The FC tablets stored in this airtight container were used as the FC tablets of Production Example 1 immediately after production.

[0071] (1.2) Production of FC tablets of Production Example 2 The FC tablets of Production Example 2 were manufactured using the same formulation as in Formulation Example 1 and the same manufacturing method as the FC tablets of Production Example 1, except that they were manufactured in a separate batch from the FC tablets of Production Example 1. After drying was completed, the temperature of the FC tablets of Production Example 2 removed from the pan coating device was measured using a non-contact thermometer (PT-7LD, manufactured by Optex FA). The temperature of the FC tablets at the end of drying was 57°C. After measuring the temperature, the FC tablets were stored in an airtight metal container until they were used in the moisture measurement and dissolution test described below. The FC tablets stored in this airtight container were used as the FC tablets of Production Example 2 immediately after production.

[0072] (1.3) Production of FC tablets of Production Example 3 The FC tablets of Production Example 3 were manufactured in the same manner as the FC tablets of Production Example 1, except that the formulation was changed to Formulation Example 2 and three lots were manufactured. Each lot was manufactured separately. The temperature of the FC tablets of each lot of Production Example 3 was measured using a non-contact thermometer (PT-7LD, manufactured by Optex FA). Measurements were performed by removing a portion of the FC tablets from the pan coating device. The temperature of the FC tablets at the end of drying varied for each lot and was 50°C, 64°C, and 75°C. The FC tablets of each lot were stored in an airtight metal container until used in the moisture measurement and dissolution test described below. The FC tablets stored in this airtight container were used as the FC tablets of Production Example 3 immediately after production.

[0073] (1.4) Production of FC tablets of Production Examples 4 to 6 The FC tablets of Production Examples 4 to 6 were manufactured in the same manner as the FC tablets of Production Example 1, except that the formulations were changed to those of Formulation Examples 3 to 5, respectively. Formulations 3 to 5 were formulations in which only the amounts of various coating agents were changed from Formulation Example 2. The temperatures of the FC tablets of Production Examples 4 to 6 were measured using a non-contact thermometer (PT-7LD, manufactured by Optex FA). The temperatures of the FC tablets of Production Examples 4 to 6 at the end of drying were 71°C, 72°C, and 73°C, respectively. After measuring the temperature, each FC tablet was stored in an airtight metal container until used in the moisture measurement and dissolution test described below. The FC tablets stored in this airtight container were used as the FC tablets of Production Examples 4 to 6 immediately after production.

[0074] 2. Moisture measurement (Karl Fischer method) The water content of each FC tablet immediately after production was measured by volumetric titration in accordance with the water content determination method (Karl Fischer method) described in the 18th Edition of the Japanese Pharmacopoeia. Specifically, the procedure was as follows: A solvent was placed in a titration bottle, and a Karl Fischer reagent was added dropwise to make the solution anhydrous. As a sample, an FC tablet was lightly crushed and added to a titration bottle. The water content was measured using a Karl Fischer reagent whose potency had been previously standardized with purified water. <Test conditions> Measuring equipment: "MKV-710" Solvent: "Hayashi Solvent FM-II Dehydrated Solvent (for sugars)" Karl Fischer reagent: "Aquamicron (registered trademark) Titrant SS-Z 3mg"

[0075] 3. Stability testing A portion of each FC tablet immediately after production in Production Examples 1 to 6 was taken, placed in a glass bottle, sealed, and stored at 50°C for 2 weeks. The drug dissolution properties of the FC tablets immediately after production and after storage were examined according to Method 2 (paddle method) of the Dissolution Test described in the 18th Edition of the Japanese Pharmacopoeia. Specifically, the test solution was prepared by adding polysorbate 80 to Dissolution Test Solution 2 (pH 6.8, Kanto Chemical Co., Ltd.) to a final concentration of 0.05%. One FC tablet immediately after production or one FC tablet after storage was added to 900 mL of test solution adjusted to a liquid temperature of 37±0.5°C and stirred at 75 rpm. 10 mL of each tablet was sampled from the test solution after 5, 10, 15, 30, 60, 120, 180, and 360 minutes. The sample solution was filtered through a membrane filter to obtain a sample solution. The concentration of eltrombopag in the sample solution was measured using an ultraviolet spectrophotometer, and the dissolution rate was calculated. Dissolution tests were performed on three tablets of each FC tablet immediately after production and after storage, and the average dissolution rate (average dissolution rate) was calculated.

[0076] 4.Results The difference between the average dissolution rate of the FC tablets immediately after production and the average dissolution rate of the FC tablets after storage (hereinafter referred to as the "difference in dissolution rates at two time points") was calculated at two appropriate time points where the average dissolution rate of the FC tablets immediately after production was approximately 40% and 85%. If this difference was 10% or less, the FC tablets were evaluated as having good storage stability. Table 2 shows the difference in dissolution rate at two time points for each FC tablet.

[0077] [Table 2]

[0078] As shown in Table 2, for the FC tablets of Production Example 1, the difference in dissolution rate at the two time points was 10% or more at all times. On the other hand, for the FC tablets of Production Example 2, the difference in dissolution rate at the two time points was within 10% at all times. The FC tablets of Production Examples 1 and 2 were manufactured separately, but the formulation and manufacturing process were the same. The FC tablets of Production Examples 1 and 2 had different tablet temperatures at the end of drying, and this difference was thought to be due to lot-to-lot variations in the drying process. Furthermore, due to the difference in temperature, the FC tablets of Production Examples 1 and 2 had different water contents. Specifically, the water content of the FC tablets of Production Example 1 was 3.6%, and the water content of the FC tablets of Production Example 2 was 2.5%. This suggests that the reason for the improvement in the difference in dissolution rate at the two time points for the FC tablets of Production Example 2 compared to the FC tablets of Production Example 1 is due to the reduced water content of the tablets. Furthermore, the moisture contents of the FC tablets of Production Example 3, in order of lowest tablet temperature at the end of drying, were 3.0%, 2.0%, and 1.5%. For these FC tablets, the difference in dissolution rate at the two time points was within 10%. Therefore, it was demonstrated that FC tablets with a moisture content of 3.0% or less have the same dissolution properties as those immediately after production, even when stored at 50°C for 2 weeks. Furthermore, for the FC tablets of Production Examples 4 to 6, the difference in dissolution rate at the two time points was within 10%. This suggests that dissolution delay can be suppressed by controlling the moisture content of the tablets, regardless of the amount of film coating.

[0079] It is generally known that the tablet temperature at the end of drying varies depending on factors such as the equipment used, the scale of production, and differences between lots. However, referring to Table 2, the higher the tablet temperature at the end of drying, the lower the moisture content in the tablet tended to be. Furthermore, it was shown that when the moisture content in the tablet is 3.0% or less, the tablet retains the same dissolution properties as immediately after production, even when stored at 50°C for 2 weeks. These findings suggest that the FC tablets formulated in Formulation Examples 1 to 5 have excellent storage stability and suppress dissolution delay when the moisture content in the tablet is controlled by drying treatment during the manufacturing process and airtight storage after production.

Claims

1. A pharmaceutical composition comprising eltrombopag or a pharmaceutically acceptable salt thereof, wherein the water content in the pharmaceutical composition is 3.5% or less.

2. 2. The pharmaceutical composition according to claim 1, wherein the water content is 3.0% or less.

3. 2. The pharmaceutical composition according to claim 1, wherein the water content is measured by the Karl Fischer method and is expressed as a mass percentage, with the mass of the pharmaceutical composition before measurement being taken as 100%.

4. 10. The pharmaceutical composition of claim 1, which is a tablet.

5. The pharmaceutical composition according to claim 4, wherein the tablet is a film-coated tablet.

6. The pharmaceutical composition according to claim 5, wherein the film-coated tablet has a water-soluble film coating layer.

7. 7. The pharmaceutical composition according to claim 6, wherein the water-soluble film coating layer comprises at least one coating agent selected from the group consisting of hypromellose, hydroxypropyl cellulose, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 20000, polysorbate 80, polyvinylpyrrolidone, titanium oxide, ethyl cellulose, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, talc, triethyl citrate, light anhydrous silicic acid, triacetin, and polyvinyl alcohol.

8. 7. The pharmaceutical composition according to claim 6, wherein the water-soluble film-coating layer comprises at least one colorant selected from yellow ferric oxide and ferric oxide.

9. The pharmaceutical composition according to claim 1, which is hermetically packaged.

10. 10. The pharmaceutical composition according to claim 9, wherein the airtight packaging is at least one selected from the group consisting of PTP packaging, strip packaging, pillow packaging, bottle packaging, and stick packaging.

11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is packaged in a PTP, and the PTP-packaged pharmaceutical composition is further packaged in a pillow package.

12. A method for producing a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, comprising the step of drying a composition containing eltrombopag or a pharmaceutically acceptable salt thereof and water so that the water content in the composition is 3.5% or less to obtain a pharmaceutical composition.

13. The method of claim 12, further comprising the step of airtightly packaging the pharmaceutical composition obtained by drying.

14. A method for suppressing delayed dissolution of a pharmaceutical composition containing eltrombopag or a pharmaceutically acceptable salt thereof, by controlling the water content of the pharmaceutical composition to be 3.5% or less.

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