Method for producing pharmaceutical composition containing edoxaban, and method for improving dissolution of edoxaban from pharmaceutical composition containing edoxaban

Abstract

To provide a method for producing an edoxaban-containing pharmaceutical composition having superior dissolution, and a method for improving dissolution of edoxaban from a pharmaceutical composition containing edoxaban.SOLUTION: A method for producing a pharmaceutical composition containing edoxaban as an active ingredient comprises the step of preparing active ingredient-containing granules including the edoxaban and a binder through a stirring granulation process, where a granulation liquid containing at least a portion of the binder is employed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing an edoxaban-containing pharmaceutical composition having excellent dissolution properties, and a method for improving the dissolution properties of edoxaban from a pharmaceutical composition containing edoxaban. [Background technology]

[0002] Edoxaban (chemical name: N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide)cyclohexyl]oxamide) competitively and selectively inhibits activated human blood coagulation factor X (FXa) (Non-Patent Document 1).

[0003] Orally disintegrating tablets that rapidly disintegrate in the mouth with saliva or a small amount of water to release the active ingredient are commercially available as formulations containing edoxaban as a medicinal ingredient (Non-Patent Document 1). Patent Document 1 describes a solid pharmaceutical composition containing a predetermined amount of edoxaban, with improved dissolution characteristics in the neutral range. Patent Document 2 describes an orally disintegrating tablet containing edoxaban that rapidly disintegrates when placed in the mouth or when placed in water.

[0004] The applicant of the present application has developed an orally disintegrating tablet of edoxaban that has excellent storage stability (Patent Document 3). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2010 / 147169 Brochure [Patent Document 2] International Publication No. 2018 / 101373 Brochure [Patent Document 3] Patent No. 5584509 [Non-patent literature]

[0006] [Non-Patent Document 1] Package insert for "Lixiana (registered trademark) Tablets 15 mg, Lixiana (registered trademark) Tablets 30 mg, Lixiana (registered trademark) Tablets 60 mg" Summary of the Invention [Problem to be solved by the invention]

[0007] As described above, various pharmaceutical compositions containing edoxaban as a medicinal ingredient have been developed, but pharmaceutical compositions with even better dissolution properties are desired. Therefore, an object of the present invention is to provide a method for producing an edoxaban-containing pharmaceutical composition having excellent dissolution properties, and a method for improving the dissolution properties of edoxaban from a pharmaceutical composition containing edoxaban. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems, and as a result have found that the dissolution of edoxaban from a pharmaceutical composition can be further improved by preparing granules containing the active ingredient edoxaban by a specific granulation method using a granulation liquid containing a binder, thereby completing the present invention. The present invention will now be described.

[0009] [1] A method for producing a pharmaceutical composition containing edoxaban as an active ingredient, comprising: a step of producing a medicinal ingredient-containing granule containing the edoxaban and a binder by a high-pressure granulation method, A method characterized in that a granulation liquid containing at least a portion of the binder is used in the agitation granulation method. [2] The method according to [1], wherein the medicinal ingredient-containing granules contain 0.1% by mass or more and 20% by mass or less of the binder. [3] The method according to [1] or [2], wherein a part of the binder is blended with the granulation liquid, and the remainder is used in powder form to produce the medicinal ingredient-containing granules. [4] The method according to [3], wherein the mass ratio of the powder binder to the binder contained in the granulation liquid is 2 times or more and 10 times or less. [5] The method according to any one of [1] to [4], wherein the binder is one or more binders selected from hydroxypropyl cellulose, hypromellose, povidone, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. [6] The method according to any one of [1] to [4] above, wherein the binder is hydroxypropyl cellulose. [7] The method according to [6], wherein the viscosity of a 2% by mass aqueous solution of the hydroxypropyl cellulose at 20°C is 2.0 mPa·s or more and 400 mPa·s or less. [8] A method for improving the dissolution of edoxaban from a pharmaceutical composition, comprising: a step of producing a medicinal ingredient-containing granule containing the edoxaban and a binder by a high-pressure granulation method, A method characterized in that a granulation liquid containing at least a portion of the binder is used in the agitation granulation method. [Effects of the Invention]

[0010] The edoxaban-containing pharmaceutical composition of the present invention has excellent dissolution properties of the active ingredient edoxaban, and therefore, after oral administration, edoxaban is released at least in the small intestine, allowing it to be efficiently absorbed. Therefore, the edoxaban-containing pharmaceutical composition of the present invention is industrially very advantageous as one form of formulation containing edoxaban as the active ingredient. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a graph showing the results of a dissolution test of edoxaban from the edoxaban tablet according to the present invention. [Figure 2] FIG. 2 is a graph showing the results of a dissolution test of edoxaban from the edoxaban tablet according to the present invention. [Figure 3] FIG. 3 is a graph showing the results of a dissolution test of edoxaban from the edoxaban tablet according to the present invention. [Figure 4] FIG. 4 is a graph showing the results of a dissolution test of edoxaban from the edoxaban tablet according to the present invention. [Figure 5] FIG. 5 is a graph showing the results of a dissolution test of edoxaban from the edoxaban tablet according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] The method for producing a pharmaceutical composition containing edoxaban as a medicinal ingredient according to the present invention includes a step of producing medicinal ingredient-containing granules containing the edoxaban and a binder by a high-pressure granulation method, and is characterized in that a granulation liquid containing at least a portion of the binder is used in the high-pressure granulation method. The present invention will be described below with specific examples, but is not limited to these examples.

[0013] The pharmaceutical composition of the present invention contains edoxaban as an active ingredient. Edoxaban has the chemical name N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl]oxamide, and has the following chemical structure. Edoxaban competitively and selectively inhibits human activated blood coagulation factor X (FXa).

[0014] [ka]

[0015] Examples of such salts include organic acid salts such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, tosylate, and trifluoromethanesulfonate; inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and acidic amino acid salts such as glutamate and aspartate, with tosylate being preferred. Edoxaban or its salts may also be solvated, with hydrates being preferred and monohydrate being more preferred. In other words, even when the term "edoxaban" is used in this disclosure, it encompasses not only the compound having the above chemical structure, but also its salts and solvates.

[0016] When a crystal is used as the starting material edoxaban, the crystalline form is not particularly limited. For example, Form I crystal or Form II crystal described in International Publication WO2011 / 115066 can be used as a crystal of edoxaban tosylate, and of these, Form I crystal is particularly preferably used.

[0017] The size of the raw material edoxaban can be adjusted appropriately. For example, the cumulative 50% particle diameter (D 50 ) can be 1 μm or more and 70 μm or less, and preferably 3 μm or more and 40 μm or less. Therefore, when the particle size of the raw material edoxaban is large, it is preferable to grind it in advance. In the present disclosure, the cumulative 50% particle size (D 50 ) shall be measured on a volume basis using a laser diffraction particle size distribution analyzer.

[0018] The amount and proportion of edoxaban in the pharmaceutical composition of the present invention may be appropriately adjusted within a range in which edoxaban can exert its effects. For example, in the case of tablets, the amount of edoxaban per tablet can be 1 mg or more and 100 mg or less, preferably 5 mg or more, more preferably 10 mg or more, and preferably 80 mg or less, more preferably 60 mg or less, and even more preferably 15 ± 0.15 mg, 30 ± 0.3 mg, 40 ± 0.4 mg, or 60 ± 0.6 mg. The proportion of edoxaban in the pharmaceutical composition can be 1% by mass or more and 50% by mass or less, preferably 2% by mass or more, more preferably 5% by mass or more, even more preferably 10% by mass or more, and preferably 40% by mass or less, more preferably 30% by mass or less, and even more preferably 20% by mass or less. Note that when a salt of edoxaban or a solvate thereof is used as a raw material, the above amounts and proportions refer to the amount and proportion of edoxaban itself, excluding counter anions and solvents.

[0019] In the present invention, active ingredient-containing granules containing edoxaban and a binder are produced by agitation granulation. The agitation granulation method involves spraying a granulation liquid, such as a solvent or binder solution or binder dispersion, onto the powder while rotating an agitator at high speed, or adding the granulation liquid from a hopper or other suitable means. Other granulation methods include fluidized bed granulation and tumbling fluidized bed granulation. Fluidized bed granulation involves fluidizing powder with hot air while spraying a solvent or binder solution or binder dispersion onto the powder. Tumbling fluidized bed granulation involves granulating particles in a fluidized bed while applying fluidizing motion due to a fluidizing gas and tumbling compaction motion due to the rotation of the agitator. Although the reason for this is not entirely clear, the inventor's experimental findings suggest that the dissolution rate of edoxaban is significantly improved by preparing active ingredient-containing granules using the agitation granulation method.

[0020] The pharmaceutical composition of the present invention may contain, in addition to the active ingredient edoxaban, general pharmaceutical additives. For example, the active ingredient-containing granules may contain, in addition to the active ingredient edoxaban, general pharmaceutical additives such as excipients, disintegrants, and binders.

[0021] Excipients are additives that are added to dilute medicinal ingredients or increase the amount of the formulation to improve the formability and ease of administration of the formulation. Examples of excipients include mannitol, crystalline cellulose, lactose, ethyl cellulose, starch, dextrin, and sucrose. A single excipient may be used, or two or more may be used in combination. The amount and proportion of the excipient in the medicinal ingredient-containing granules may be adjusted appropriately depending on the dosage form, and can be, for example, 10% by mass or more and 70% by mass or less, preferably 20% by mass or more, and preferably 60% by mass or less.

[0022] Edoxaban may be first mixed with an excipient to form a triturated mixture. Trituration can improve the uniformity of edoxaban. The proportion of edoxaban in the triturated mixture can be adjusted as appropriate. For example, the proportion of edoxaban relative to the total weight of edoxaban and excipients can be set to 30% by weight or more and 50% by weight or less.

[0023] Disintegrants are ingredients that are incorporated to absorb moisture and promote disintegration of the pharmaceutical composition, facilitating the release of the medicinal ingredients. Examples of disintegrants include, but are not limited to, croscarmellose sodium, carmellose, starch, sodium starch glycolate, carmellose sodium, carmellose calcium, light anhydrous silicic acid, and crospovidone. A single disintegrant may be used, or two or more may be combined. The amount and proportion of disintegrant in the medicinal ingredient-containing granules may be adjusted appropriately depending on the dosage form, but can be, for example, 1% by mass or more and 20% by mass or less, preferably 2% by mass or more, more preferably 4% by mass or more, and preferably 15% by mass or less.

[0024] Binders are added to bind various components and increase the strength of granules or tablets. Binders are not particularly limited, but examples include hydroxypropyl cellulose, hypromellose, povidone, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose polyvinylpyrrolidone, polyvinyl alcohol, and ethyl cellulose. A single binder may be used, or two or more may be used in combination. The amount and proportion of binder in the medicinal ingredient-containing granules may be adjusted appropriately depending on the dosage form, but may be, for example, 0.05% by mass or more and 20% by mass or less. The proportion is preferably 0.1% by mass or more or 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 2% by mass or more, and preferably 15% by mass or less, and more preferably 10% by mass or less. The amount of binder may be adjusted as appropriate, for example, to 0.01 to 0.5 parts by mass per 1 part by mass of the active ingredient edoxaban. Furthermore, the ratio of binder per 1 part by mass of edoxaban may be 0.1 to 10 parts by mass. The ratio is preferably 0.3 parts by mass or more, more preferably 0.5 parts by mass or more, and is preferably 5 parts by mass or less, more preferably 2 parts by mass or less.

[0025] The binder is preferably one or more binders selected from hydroxypropyl cellulose, hypromellose, povidone, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, with hydroxypropyl cellulose being more preferred. In particular, incorporating hydroxypropyl cellulose as at least a portion of the binder can further improve the dissolution of edoxaban. It is preferable to use relatively fine hydroxypropyl cellulose. For example, a 2% by mass aqueous solution preferably has a viscosity of 1.0 mPa·s or more and 500 mPa·s or less at 20°C. The viscosity is preferably 2.0 mPa·s or more, and 400 mPa·s or less, more preferably 100 mPa·s or less or 10 mPa·s or less, and even more preferably 6.0 mPa·s or less or 3.0 mPa·s or less.

[0026] In the present invention, edoxaban is granulated using a granulation liquid containing at least a portion of a binder to produce granules containing a medicinal ingredient. The solvent for the granulation liquid can be water or a mixed solvent of water and a water-miscible organic solvent. The water-miscible organic solvent refers to an organic solvent that is fully miscible with water, such as an alcoholic solvent such as ethanol or 2-propanol, with ethanol being preferred. The proportion of the water-miscible organic solvent in the mixed solvent is preferably 50% by mass or less or 40% by mass or less, more preferably 20% by mass or less or 10% by mass or less, and even more preferably 5%, 2%, or 1% by mass or less.

[0027] The granulation liquid may be a solution or dispersion of the binder. A solution refers to a liquid in which the binder is uniformly dissolved in a solvent, and a dispersion refers to a liquid in which at least a portion of the binder is dispersed in the solvent as a solid.

[0028] In the present invention, at least a portion of the binder may be blended into the granulation liquid for granulating edoxaban, and the entire amount of the binder may be blended into the granulation liquid, or a portion of the binder may be dissolved or dispersed in water to prepare the granulation liquid, and the remainder may be granulated together with edoxaban in powder form. In the latter case, the ratio of the binder in the granulation liquid to the total binder can be 5% by mass or more and 50% by mass or less.

[0029] An acidic amino acid may be added to the medicinal ingredient-containing granules. The addition of an acidic amino acid can suppress changes in tablet thickness and hardness during storage, improving storage stability. Examples of acidic amino acids include aspartic acid and glutamic acid. Although only one type of acidic amino acid may be used, or two or more types may be used in combination, aspartic acid is preferably used. Furthermore, L-acidic amino acids are preferred as acidic amino acids.

[0030] The amount of acidic amino acid may be adjusted as appropriate, but may be, for example, 0.1% by mass or more and 10% by mass or less relative to the total amount of the active ingredient-containing granules. The proportion is preferably 0.5% by mass or more, more preferably 1% by mass or more, even more preferably 1.5% by mass or more, and preferably 8% by mass or less, more preferably 5% by mass or less, and even more preferably 3% by mass or less. The amount of acidic amino acid may be 1% by mass or more and 20% by mass or less relative to edoxaban. The proportion is preferably 1.5% by mass or more, more preferably 2% by mass or more, even more preferably 4% by mass or more, and preferably 15% by mass or less, and more preferably 10% by mass or less.

[0031] The size of the granules containing the active ingredient may be adjusted as appropriate. For example, the average particle diameter (D 50 ) can be 30 μm or more and 300 μm or less, and preferably 50 μm or more and 200 μm or less.

[0032] The medicinal ingredient-containing granules may be further mixed with common pharmaceutical additives, such as lubricants, flow agents, sweeteners, flavorings, etc., in addition to the above-mentioned excipients, disintegrants, and binders.

[0033] Lubricants are added to adhere to the surfaces of each component to increase its fluidity, prevent the components from adhering to the equipment, and facilitate tableting. The lubricant is not particularly limited, but examples include magnesium stearate, talc, hydrogenated vegetable oil, polyglycerol fatty acid ester, and sucrose fatty acid ester. A single lubricant may be used, or two or more may be used in combination, with magnesium stearate being preferred. The amount and proportion of the lubricant can be adjusted as appropriate, but can be, for example, 0.01% by mass or more and 10% by mass or less of the total pharmaceutical composition. The proportion is preferably 0.2% by mass or more, more preferably 0.5% by mass or more, and preferably 5% by mass or less, and more preferably 2% by mass or less.

[0034] A fluidizer is a component added to increase the fluidity of each component so that they can be mixed uniformly and quickly. The fluidizer is not particularly limited, and examples thereof include light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, and talc. A single fluidizer may be used, or two or more may be used in combination. The amount and proportion of the fluidizer may be adjusted as appropriate, and may be, for example, 0.1% by mass or more and 10% by mass or less, preferably 0.2% by mass or more, more preferably 0.5% by mass or more, and preferably 5% by mass or less, and more preferably 2% by mass or less, based on the total weight of the pharmaceutical composition.

[0035] Sweeteners are ingredients that are added to reduce the bitterness of pharmaceutical composition ingredients. Sweeteners are not particularly limited, and examples include aspartame, saccharin, erythritol, and sucrose. Only one type of sweetener may be used, or two or more types may be combined. The amount and proportion of sweetener may be adjusted as appropriate, and may be, for example, 0.1% by mass or more and 10% by mass or less of the total pharmaceutical composition, preferably 0.2% by mass or more, more preferably 0.5% by mass or more, and preferably 5% by mass or less, and more preferably 2% by mass or less.

[0036] Flavorings are components that impart a fragrance to a pharmaceutical composition. The flavorings are not particularly limited, and examples include peppermint micron, yogurt flavoring, peach flavoring, grapefruit flavoring, apple flavoring, acerola flavoring, plum flavoring, plum flavoring, coffee flavoring, and black tea flavoring. A single flavoring may be used, or two or more may be used in combination. The amount and proportion of flavoring may be adjusted as appropriate. While even a small amount of flavoring can produce a pleasant aroma, too much may make the pharmaceutical composition difficult to take. Therefore, it is preferable to use a small amount, for example, 0.5% by mass or less of the total pharmaceutical composition.

[0037] The active ingredient-containing granules may be mixed with rapidly disintegrating granules. The rapidly disintegrating granules are granules that absorb moisture in the oral cavity to rapidly promote disintegration of the orally disintegrating tablet of the present invention and accelerate the release of the active ingredient edoxaban. The rapidly disintegrating granules contain at least an excipient and a disintegrant. In addition, they may contain a coloring agent.

[0038] The excipients to be blended in the rapidly disintegrating granules may be the same as those to be blended in the granules containing a medicinal ingredient, but they may be the same or different. The amount of excipient in the rapidly disintegrating granules may be adjusted appropriately, and may be, for example, 50% by mass or more and 95% by mass or less of the total amount of the rapidly disintegrating granules, preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 90% by mass or less, and even more preferably 80% by mass or less.

[0039] The disintegrant contained in the rapidly disintegrating granules may be the same as the disintegrant contained in the medicinal ingredient-containing granules, but they may be the same or different. The amount of disintegrant in the rapidly disintegrating granules may be adjusted appropriately, and may be, for example, 10% by mass or more and 50% by mass or less, preferably 15% by mass or more, more preferably 20% by mass or more, and preferably 40% by mass or less, more preferably 30% by mass or less, based on the total amount of the rapidly disintegrating granules.

[0040] The binder to be incorporated into the rapidly disintegrating granules may be the same as the binder to be incorporated into the active ingredient-containing granules, but the two may be the same or different. The amount of binder in the rapidly disintegrating granules may be adjusted as appropriate, and may be, for example, 0.1% by mass or more and 15% by mass or less based on the total amount of the rapidly disintegrating granules. The proportion is preferably 1% by mass or more, more preferably 2% by mass or more, even more preferably 5% by mass or more, and is preferably 10% by mass or less, more preferably 8% by mass or less.

[0041] The rapidly disintegrating granules may contain a colorant. The colorant to be incorporated into the rapidly disintegrating granules is not particularly limited, and examples thereof include metal oxides such as ferric oxide, yellow ferric oxide, titanium oxide, and zinc oxide; talc; and barium sulfate. A single colorant may be used, or two or more types may be used in combination. The amount and proportion of the colorant may be appropriately adjusted, for example, within a range that allows the rapidly disintegrating granules or the entire tablet to be colored. A very small amount may be used, for example, 0.01% by mass or more and 0.5% by mass or less of the total rapidly disintegrating granules.

[0042] The size of the rapidly disintegrating granules may be adjusted appropriately. For example, the average particle diameter (D 50 ) can be 30 μm or more and 200 μm or less, and preferably 40 μm or more and 150 μm or less.

[0043] The excipients and disintegrants to be mixed with the medicinal ingredient-containing granules and the rapidly disintegrating granules may be the same as the excipients and disintegrants to be blended in the medicinal ingredient-containing granules and the rapidly disintegrating granules, but they may be the same or different.

[0044] The dosage form of the edoxaban-containing pharmaceutical composition of the present invention is not particularly limited, and examples include tablets, fine granules, and dry syrup. Examples of tablets include general tablets produced by mixing granules containing the active ingredient edoxaban with other ingredients such as a lubricant and compressing the mixture, as well as orally disintegrating tablets, which are compression-molded products containing active ingredient-containing granules, rapidly disintegrating granules, and lubricant-containing mixtures. Fine granules are primarily composed of edoxaban-containing granules. Dry syrup can be taken by dispersing it in water.

[0045] The edoxaban-containing pharmaceutical composition of the present invention can be produced by a general method depending on its dosage form, etc. For example, the edoxaban-containing tablet of the present invention can be produced by mixing the active ingredient-containing granules with other pharmaceutical additives such as a lubricant and compressing the mixture, and in particular, the edoxaban-containing orally disintegrating tablet of the present invention can be produced by a method comprising a step of mixing the active ingredient-containing granules, the rapidly disintegrating granules, and at least a lubricant and compressing the mixture.

[0046] The active ingredient-containing granules and the rapidly disintegrating granules can be produced according to a general granule production method as long as the active ingredient-containing granules contain edoxaban as the active ingredient, but at least the active ingredient-containing granules are prepared by a stirring granulation method using a granulation liquid containing a binder.

[0047] The water content of the edoxaban-containing pharmaceutical composition of the present invention is not particularly limited, but it is preferable to adjust the manufacturing conditions of each granule so that the water content is 5% by mass or less. The water content is preferably 3% by mass or less. The lower limit of the water content is not particularly limited and may be 0% by mass, but the water content can be, for example, 0.1% by mass or more. The water content can be measured, for example, by the Karl Fischer method.

[0048] The hardness of the edoxaban-containing tablet according to the present invention is not particularly limited, but is preferably 20 N or more and 100 N or less. The hardness can be adjusted, for example, by the tableting pressure.

[0049] The size of the edoxaban-containing tablet of the present invention may be adjusted appropriately. For example, the tablet may be disc-shaped or lenticular-shaped for easy oral administration, with a diameter of 4 mm to 10 mm and a thickness of 2 mm to 5 mm. The tablet may also be oval or oval-like, with a major axis of 10 mm to 15 mm and a thickness of 5 mm to 10 mm.

[0050] The edoxaban-containing pharmaceutical composition of the present invention may be packaged in a packaging material, such as a press-through package (PTP), a strip package, a bottle, or an aluminum package.

[0051] Examples of materials for PTP packaging that contain tablets and the like include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, and metals such as aluminum. These materials may be used alone or in combination. Examples of material combinations include a laminate of polyvinyl chloride and polyvinylidene chloride, and a laminate of polyvinyl chloride and polychlorotrifluoroethylene. Tablets can be PTP-packaged by forming a resin sheet with pockets using a known method, placing tablets in the pockets, and then covering them with aluminum foil.

[0052] The PTP package may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain a desiccant and / or oxygen scavenger. Examples of desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite. Examples of oxygen scavengers include iron-based oxygen scavengers such as iron powder, and organic oxygen scavengers such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol. Only one type of desiccant and / or oxygen scavengers may be used, or multiple types may be used in combination. A desiccant and an oxygen scavenger may also be used in combination. An example of a product combining a desiccant and an oxygen scavenger is PharmaKeep (registered trademark) (manufactured by Mitsubishi Gas Chemical Company, Inc.).

[0053] The edoxaban-containing pharmaceutical composition of the present invention may be filled in a glass or plastic bottle. Examples of materials for the plastic bottle include the resins exemplified above for PTP packaging. The edoxaban-containing pharmaceutical composition of the present invention may be packaged in aluminum packaging for each dose. The aluminum packaging may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain the above-mentioned desiccant and / or oxygen scavenger.

[0054] As packaging for the edoxaban-containing pharmaceutical tablet according to the present invention, polyvinyl chloride PTP packaging and plastic bottles are particularly preferred.

[0055] The dosage of the edoxaban-containing pharmaceutical composition of the present invention may be adjusted appropriately depending on the patient's symptoms, severity, age, sex, etc. For example, in terms of the dosage of edoxaban, 20 mg or more and 80 mg or less may be administered once or twice a day, and the dosage may be reduced or increased depending on concomitant medications, etc. When a salt or solvate of edoxaban is administered, the amount is calculated in terms of edoxaban only.

[0056] As described above, in the present invention, the dissolution property of edoxaban from a pharmaceutical composition is significantly improved by producing active ingredient-containing granules containing edoxaban and a binder by a high-pressure granulation method using a granulation liquid containing at least a portion of the binder. That is, the method for improving the dissolution property of edoxaban from a pharmaceutical composition according to the present invention includes a step of producing active ingredient-containing granules containing edoxaban and a binder by a high-pressure granulation method, and is characterized in that a granulation liquid containing at least a portion of the binder is used in the high-pressure granulation method. [Example]

[0057] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is possible to carry out the invention by making appropriate modifications within the scope of the above and below-described aims, and all such modifications are included in the technical scope of the present invention.

[0058] Example 1: Examination of granulation methods for granules containing active ingredients (1) Agitation granulation method Edoxaban tablets having the composition shown in Table 1 were prepared. Specifically, the components for the triturated powder were mixed and then triturated using a disintegrator. Next, the components for the medicinal ingredient-containing granules were added to a stirring granulator and mixed, and then purified water was added to granulate. The resulting particles were crushed, dried using a fluidized bed granulator, and then sized to obtain an average particle diameter D 50 Granules containing medicinal ingredients with a particle size of 100 μm were prepared. The granules containing the active ingredient were mixed with magnesium stearate and then compressed into tablets to obtain edoxaban tablets with a hardness of 50N.

[0059] (2) Fluidized bed granulation method The ingredients for the dilution powder were mixed and then dilution was carried out using a disintegrator. Next, the dilution powder, D-mannitol, partially pregelatinized starch, and hydroxypropyl cellulose were placed in a fluidized bed granulator, and granulation was carried out by spraying a dispersion of crospovidone and partially pregelatinized starch (dispersion liquid) in purified water. The resulting particles were dried and sized to an average particle diameter D 50 The resulting granules containing the active ingredient had a water content of 1.9% by mass. The granules containing the active ingredient were mixed with magnesium stearate and then compressed into tablets to obtain edoxaban tablets with a hardness of 52N.

[0060] [Table 1]

[0061] (3) Elution test Dissolution tests were conducted in accordance with the 18th edition of the Japanese Pharmacopoeia. Specifically, 900 mL of pH 6.8 phosphate buffer was used as the dissolution test medium, and the test was conducted for 60 minutes using the paddle method at a paddle rotation speed of 50 rpm. The results are shown in Figure 1.

[0062] As shown in Figure 1, when the active ingredient-containing granules were granulated by the agitation granulation method, the dissolution of the active ingredient, edoxaban, was superior to that when they were granulated by the fluidized bed granulation method. For tablets manufactured using the agitation granulation method, the paddle rotation speed was increased from 50 rpm to 200 rpm after 60 minutes, and the dissolution rate was measured after 70 minutes. However, the dissolution rate was almost the same as that after 60 minutes, indicating that edoxaban had been sufficiently dissolved even after 60 minutes.

[0063] Example 2: Preparation of orally disintegrating edoxaban tablets and dissolution test Edoxaban orally disintegrating tablets were manufactured with the compositions shown in Table 2. In the table, "powder added" indicates that powdered hydroxypropyl cellulose was added as is, and "liquid added" indicates that hydroxypropyl cellulose was added in the form of an aqueous solution. Specifically, in Formulation Example 1, the ingredients for the medicinal ingredient-containing granules were charged into a stirring granulator and mixed, and then purified water was added to granulate. In Formulation Example 2, hydroxypropyl cellulose was dissolved in purified water to prepare a 1% by mass aqueous solution, and the ingredients other than hydroxypropyl cellulose were placed in a stirring granulator and mixed, after which the aqueous hydroxypropyl cellulose solution was added and granulated. Next, the particles obtained in Formulation Example 1 or Formulation Example 2 were crushed, dried using a fluidized bed granulator, and then sized to obtain an average particle diameter D 50 Granules containing active ingredients with a particle size of 77 to 78 μm were prepared.

[0064] D-mannitol, ethyl cellulose, and light anhydrous silicic acid were placed in a fluidized bed granulator, and a dispersion of corn starch, crospovidone, and ferric oxide in purified water was sprayed onto the mixture. The resulting particles were dried and sized to prepare rapidly disintegrating granules.

[0065] The active ingredient-containing granules, rapidly disintegrating granules, and aspartame were mixed, and then magnesium stearate was added and the mixture was compressed into tablets to obtain orally disintegrating edoxaban tablets with a hardness of 44 to 51 N.

[0066] [Table 2]

[0067] The resulting edoxaban orally disintegrating tablets were subjected to a dissolution test in accordance with the 18th edition of the Japanese Pharmacopoeia. Specifically, the test was conducted for 60 minutes using 900 mL of pH 6.8 phosphate buffer solution at a paddle rotation speed of 50 rpm. The results are shown in Figure 2.

[0068] As shown in Figure 2, it was found that the dissolution of edoxaban from tablets was superior when granulation was performed using an aqueous solution of hydroxypropyl cellulose (Formulation Example 2) compared to when granulation was performed using the binder hydroxypropyl cellulose in powder form to form granules containing the active ingredient edoxaban (Formulation Example 1).

[0069] Example 3 Edoxaban orally disintegrating tablets having the composition shown in Table 3 were prepared. Specifically, in Formulation Example 3, the ingredients for the triturated powder were mixed and then triturated using a disintegrator. Thereafter, the ingredients for the medicinal ingredient-containing granules were added to a stirring granulator and mixed, and then purified water was added to granulate. In Formulation Example 4, a dilute powder was prepared in the same manner as in Formulation Example 3. Then, hydroxypropyl cellulose was dissolved in purified water to prepare a 1% by mass aqueous solution, and the ingredients other than the hydroxypropyl cellulose liquid additive were charged into a stirring granulator and mixed, followed by adding the aqueous hydroxypropyl cellulose solution and granulating. The resulting particles are then crushed, dried using a fluidized bed granulator, and sized to an average particle diameter D 50 Granules containing active ingredients with particle sizes of 69 to 111 μm were prepared. The active ingredient-containing granules, crospovidone, carmellose, light anhydrous silicic acid, and aspartame were mixed, and then magnesium stearate was added, followed by tableting to obtain orally disintegrating edoxaban tablets with a hardness of 35N. The dissolution properties of the obtained tablets were tested in the same manner as in Example 1(3), and the results are shown in Figure 3.

[0070] [Table 3]

[0071] As shown in Figure 3, it was found that the dissolution of edoxaban from tablets was superior when part of the hydroxypropyl cellulose was added in powder form and the remaining part was used as an aqueous solution for granulation (Formulation Example 4) compared to when the binder hydroxypropyl cellulose was added in powder form to form granules containing the active ingredient edoxaban (Formulation Example 3).

[0072] Example 4 Edoxaban orally disintegrating tablets having the composition shown in Table 4 were prepared. Specifically, in Formulation Example 5, hydroxypropyl cellulose was dissolved in purified water to prepare a 1% by mass aqueous solution, and the ingredients other than hydroxypropyl cellulose were added to an agitator granulator and mixed, and then the hydroxypropyl cellulose aqueous solution was added and granulated. In Formulation Example 5, hydroxypropyl cellulose was dissolved in purified water to prepare a 1% by mass aqueous solution, and the ingredients other than the hydroxypropyl cellulose liquid additive were added to a stirring granulator and mixed, followed by adding the aqueous hydroxypropyl cellulose solution and granulating. The resulting particles are then crushed, dried using a fluidized bed granulator, and sized to an average particle diameter D 50 Granules containing the active ingredient having a particle size of 93 μm were prepared. The active ingredient-containing granules, crospovidone, carmellose, light anhydrous silicic acid, and aspartame were mixed, and then magnesium stearate was added and the mixture was compressed into tablets to obtain orally disintegrating edoxaban tablets with a hardness of 47N. The dissolution properties of the obtained tablets and the tablets of Formulation Example 4 produced in Example 3 were tested in the same manner as in Example 1(3). The results are shown in FIG.

[0073] [Table 4]

[0074] As shown in Figure 4, compared to the case where a solution of the binder hydroxypropyl cellulose is used to granulate granules containing the active ingredient edoxaban (Formulation Example 5), the case where part of the hydroxypropyl cellulose is added in powder form and the remaining part is granulated using an aqueous solution (Formulation Examples 4 and 6) resulted in superior dissolution of edoxaban from the tablets. Furthermore, it was revealed that dissolution could be further improved by increasing the ratio of powdered hydroxypropyl cellulose to liquid hydroxypropyl cellulose (Formulation Example 6).

[0075] Example 5 Hydroxypropyl cellulose was used, with a molecular weight of 40,000 and a 2% aqueous solution with a viscosity of 2 to 2.9 mPa·s at 20°C ("HPC-SSL," manufactured by Nippon Soda Co., Ltd.), or with a molecular weight of 620,000 and a viscosity of 150 to 400 mPa·s ("HPC-M," manufactured by Nippon Soda Co., Ltd.). Tablets were prepared in the same manner as in Example 1(3), except that granules containing the active ingredient edoxaban were granulated using each hydroxypropyl cellulose solution. The dissolution properties of the resulting tablets were tested in the same manner as in Example 1(3). The results are shown in Figure 5.

[0076] [Table 5]

[0077] As shown in Figure 5, it was clear that the use of finer hydroxypropyl cellulose could further improve the dissolution of edoxaban from tablets.

Claims

1. A method for producing a pharmaceutical composition containing edoxaban as an active ingredient, comprising: a step of producing a medicinal ingredient-containing granule containing the edoxaban and a binder by a high-pressure granulation method, A method characterized in that a granulation liquid containing at least a portion of the binder is used in the agitation granulation method.

2. The method according to claim 1, wherein the medicinal ingredient-containing granules contain 0.1% by mass or more and 20% by mass or less of the binder.

3. The method according to claim 1, wherein a part of the binder is blended with the granulation liquid, and the remainder is used in powder form to produce the medicinal ingredient-containing granules.

4. The method according to claim 3, wherein the mass ratio of the powdered binder to the binder contained in the granulation liquid is 2 to 10 times.

5. 2. The method of claim 1, wherein the binder is one or more binders selected from hydroxypropyl cellulose, hypromellose, povidone, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

6. The method of claim 1 wherein the binder is hydroxypropyl cellulose.

7. The method according to claim 6, wherein the viscosity of a 2% by mass aqueous solution of the hydroxypropyl cellulose at 20°C is 2.0 mPa·s or more and 400 mPa·s or less.

8. A method for improving the dissolution of edoxaban from a pharmaceutical composition, comprising: a step of producing a medicinal ingredient-containing granule containing the edoxaban and a binder by a high-pressure granulation method, A method characterized in that a granulation liquid containing at least a portion of the binder is used in the agitation granulation method.

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