Vonoprazan fumarate containing granules

Abstract

Providing granules or solid formulations with reduced dissolution delay of Vonoprazan Fumarate after storage SOLUTION: The disclosed granules or solid formulations comprise Vonoprazan Fumarate, carbonate and aspartic acid.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to vonoprazan fumarate-containing granules. [Background technology]

[0002] Vonoprazan is a drug known as 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine. Vonoprazan fumarate is approved in Japan as a treatment for gastric ulcers, duodenal ulcers, reflux esophagitis, and other conditions. Patent Document 1 discloses in its Examples (Table 12) granules containing vonoprazan fumarate and sodium bicarbonate. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2022 / 124243 Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have thoroughly studied the formulation disclosed in Patent Document 1. As a result, they have newly discovered a problem that when the amount of sodium bicarbonate is further increased beyond the range disclosed in Patent Document 1 for the purpose of extending the lag time until the drug is released after ingestion, the dissolution of vonoprazan fumarate after storage is delayed.

[0005] An object of one aspect of the present invention is to provide a granule or solid preparation in which the delay in dissolution of vonoprazan fumarate after storage is reduced. [Means for solving the problem]

[0006] The present invention includes the following aspects. <1> Contains vonoprazan fumarate, carbonate, and aspartic acid, Granules. <2> The carbonate is one or more selected from the group consisting of potassium carbonate, precipitated calcium carbonate, sodium bicarbonate, dry sodium carbonate, sodium carbonate hydrate, and magnesium carbonate. <1> The granules described in <3> The granules each include, in this order from the center to the outer shell, a vonoprazan fumarate-containing core, an intermediate layer, and a coating layer. <1> or <2> The granules described in <4> a separating layer is further provided between the vonoprazan fumarate-containing core and the intermediate layer. <3> The granules described in <5> the aspartic acid is contained in the vonoprazan fumarate-containing core; The carbonate is contained in the intermediate layer. <3> or <4> The granules described in <6> When the content of the vonoprazan fumarate is 100% by weight, the content of the carbonate is 30% by weight or more. <1> ~ <5> The granules according to any one of the preceding items. <7> When the content of the carbonate is 100% by weight, the content of the aspartic acid is 15% by weight or more. <1> ~ <6> The granules according to any one of the preceding items. <8> <1> ~ <7> The granules according to any one of Solid dosage forms. <9> It is a tablet, <8> 1. A solid formulation according to claim 1. <10> Contains vonoprazan fumarate, carbonate, and aspartic acid, Solid dosage forms. <11> granulating raw materials containing vonoprazan fumarate, carbonate, and aspartic acid into granules; Method for manufacturing granules. <12> granulating raw materials containing vonoprazan fumarate, carbonate, and aspartic acid into granules; A method for reducing the delay in dissolution of vonoprazan fumarate from a granule or solid dosage form after storage. [Effects of the Invention]

[0007] According to one aspect of the present invention, there is provided a granule or solid formulation in which the dissolution delay of vonoprazan fumarate after storage is reduced. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is a graph showing the dissolution behavior of vonoprazan fumarate after storage. [Figure 2] 1 is a graph showing the dissolution behavior of vonoprazan fumarate after storage. DETAILED DESCRIPTION OF THE INVENTION

[0009] An embodiment of the present invention will be described below. However, the present invention is not limited to the configurations described below. The present invention can be modified in various ways within the scope of the claims. The technical scope of the present invention also extends to embodiments or examples obtained by appropriately combining multiple technical means disclosed in this specification. In this case, multiple technical means may be disclosed across multiple embodiments or examples.

[0010] Unless otherwise specified in this specification, the expression "A to B" representing a range of numerical values ​​means "greater than or equal to A and less than or equal to B."

[0011] [1. Granules] Granules according to one embodiment of the present invention contain vonoprazan fumarate, carbonate, and aspartic acid. Research by the present inventors has revealed that the combination of these three components can reduce the delay in dissolution after storage.

[0012] 1.1. Granule composition The granules contain vonoprazan fumarate, carbonate, and aspartic acid. The granules may contain other ingredients such as additives. Each of these ingredients may contain only one type, or two or more types.

[0013] [1.1.1. Vonoprazan fumarate, carbonate, and aspartate] Vonoprazan fumarate is a salt of vonoprazan and fumaric acid. Typically, vonoprazan and fumaric acid form a salt in a 1:1 molar ratio. Vonoprazan fumarate is a commonly used form of pharmaceuticals containing vonoprazan as an active ingredient and is well known to those skilled in the art, so a detailed description will be omitted.

[0014] Carbonates are carbonate ions (CO3 2- ) and any cation, and is a pharmaceutically acceptable salt. Carbonates also include bicarbonates. Examples of carbonates include potassium carbonate (K2CO3), precipitated calcium carbonate (CaCO3), sodium bicarbonate (NaHCO3), dry sodium carbonate (Na2CO3), sodium carbonate hydrate (Na2CO3·10H2O), and magnesium carbonate (MgCO3). The magnesium carbonate may be hydrated basic magnesium carbonate, hydrated normal magnesium carbonate, or a mixture thereof. In one embodiment, the carbonate is sodium bicarbonate and / or magnesium carbonate. The carbonates exemplified above are substances listed in the Japanese Pharmacopoeia and are well known to those skilled in the art, so detailed explanations of each will be omitted.

[0015] Aspartic acid is an amino acid with the formula (COOH)(NH2)CH-CH2-COOH. Aspartic acid is usually in the L-form.

[0016] In the granules, the lower limit of the carbonate content may be 30% by weight or more, 33% by weight or more, or 35% by weight or more, relative to 100% by weight of the vonoprazan fumarate content. The upper limit of the carbonate content may be 200% by weight or less, 100% by weight or less, or 50% by weight or less, relative to 100% by weight of the vonoprazan fumarate content. If the carbonate content is within the above range, the lag time from ingestion to drug release can be sufficiently extended.

[0017] In the granules, the lower limit of the aspartic acid content may be 15% by weight or more, 20% by weight or more, 25% by weight or more, or 30% by weight or more, relative to 100% by weight of the carbonate content. The upper limit of the aspartic acid content may be 200% by weight or less, 150% by weight or less, 100% by weight or less, or 50% by weight or less, relative to 100% by weight of the carbonate content. If the aspartic acid content is within the above range, dissolution delay after storage can be sufficiently reduced.

[0018] In particular, if both the carbonate content and the aspartic acid content are within the above ranges, it is preferable because both the effect of extending the lag time and the effect of reducing the delay in dissolution after storage can be expected.

[0019] In one embodiment, the D of vonoprazan fumarate contained in the granules 50 The upper limit of the cumulative 50% particle diameter on a volume basis may be 50 μm or less, 25 μm or less, or 15 μm or less. Granules can be suitably produced if the particles are fine to this extent. 50 is calculated from the particle size distribution obtained according to the particle size measurement method by laser diffraction in the particle size measurement method of the Japanese Pharmacopoeia, 17th Edition.

[0020] [1.1.2. Other ingredients] In addition to the three components described above, the granules may contain other components such as additives. Examples of such components include excipients, disintegrants, binders, lubricants or flow agents (anti-adhesion agents), colorants, flavorings, sweeteners, preservatives or antiseptics, and coating agents. Only one type of these components may be contained, or two or more types may be contained.

[0021] Examples of excipients include sugars (lactose hydrate, sucrose, maltose, fructose, glucose, trehalose, etc.), sugar alcohols (mannitol (particularly D-mannitol), maltitol, sorbitol, xylitol, erythritol, lactitol, etc.), starches (starch, pregelatinized starch, partially pregelatinized starch, etc.), celluloses (crystalline cellulose, etc.), dextrin, dextran, glycerin fatty acid esters, inorganic powders (magnesium aluminometasilicate, synthetic hydrotalcite, etc.).

[0022] Examples of binders include povidone, celluloses (methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (hypromellose), croscarmellose sodium, etc.), starch, gelatin, agar, thickening polysaccharides (alginic acid, sodium alginate, tragacanth, xanthan gum, gum arabic, pullulan, dextrin, etc.), polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyethylene oxide, copolyvidone, polyoxyethylene hydrogenated castor oil, polymers containing N-isopropylacrylamide and / or derivatives having a hydrophobic group introduced at the N-position of acrylamide, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol (including partially saponified polyvinyl alcohol), basic (meth)acrylate copolymer, and polyethylene glycol.

[0023] Examples of disintegrants include crospovidone, celluloses (carboxymethyl cellulose (carmellose), carmellose sodium, carmellose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crystalline cellulose, etc.), starches (starch, pregelatinized starch, partially pregelatinized starch, carboxymethyl starch sodium, carboxystarch sodium, hydroxypropyl starch, etc.), dextrin, calcium silicate, calcium citrate, and light anhydrous silicic acid.

[0024] Examples of lubricants or fluidizing agents (anti-adherents) include stearic acid, stearates (magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, etc.), sodium stearyl fumarate, glycerin monostearate, glycerin palmitostearate, sodium lauryl sulfate, polyethylene glycol, talc, glycerin fatty acid esters, sucrose fatty acid esters, sodium potassium tartrate, carnauba wax, L-leucine, polyethylene glycol, hydrogenated oils, silicate compounds (light anhydrous silicic acid, magnesium aluminum metasilicate, hydrous silicon dioxide, synthetic aluminum silicate, etc.), and titanium oxide.

[0025] Examples of coloring agents include yellow ferric oxide, ferric oxide, titanium oxide, black ferric oxide, food tar dyes, and natural dyes (beta-carotene, riboflavin, etc.).

[0026] Examples of sweeteners include sucralose, mannitol, sucrose, aspartame, stevia, and acesulfame potassium.

[0027] Examples of flavorings include peppermint, l-menthol, lemon micron, strawberry micron, peppermint micron, peach micron, lychee micron, and pineapple micron.

[0028] Examples of preservatives or antiseptics include ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, benzoic acid, and sodium benzoate.

[0029] (coating agent) Examples of coating agents include water-insoluble polymers. In this specification, the category of "water-insoluble polymers" includes polymers that are not soluble in water at all, as well as polymers that are poorly soluble in water.

[0030] Examples of water-insoluble polymers include cellulose-based coating agents (methyl cellulose, ethyl cellulose, carboxymethylethyl cellulose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, etc.), vinyl-based polymers (polyvinyl acetal diethylaminoacetate, polyvinyl acetate phthalate, etc.), methacrylate polymers or methacrylic acid polymers, and polysiloxane-based coating agents (dimethylpolysiloxane, dimethylpolysiloxane-silicon dioxide mixture, etc.).

[0031] Of the above, methacrylate polymers or methacrylic acid polymers, and cellulose-based coating agents (especially ethyl cellulose) are preferred, and methacrylate polymers or methacrylic acid polymers are more preferred.

[0032] There are many types of commercially available methacrylate polymers or methacrylic acid polymers, such as the Eudragit E series, Eudragit L series, Eudragit S series, Eudragit R series, Eudragit NE series, and Eudragit FS series (all of which are registered trademarks of Evonik Rohm GmbH). More specific examples include aminoalkyl methacrylate copolymer E (Eudragit E100, EPO, etc.), methacrylic acid copolymer LD (Eudragit L30D-55, L100-55, etc.), methacrylic acid copolymer L (Eudragit L100, etc.), methacrylic acid copolymer S (Eudragit S100, etc.), ammonioalkyl methacrylate copolymer (Eudragit RL100, RLPO, RS100, RSPO, RL30D, RS30D, etc.), and ethyl acrylate-methyl methacrylate copolymer (Eudragit NE30D, etc.).

[0033] One or more additives may be used in combination with the coating agent. Examples of such additives include plasticizers, binders, flow agents or lubricants (anti-adherent agents), colorants, and sweeteners. For example, a coating layer containing the coating agent and these additives may be provided on the granules.

[0034] Examples of plasticizers include polyethylene glycol, propylene glycol, glycerin, glycerin fatty acid esters (such as triacetin (glycerin triacetate)), liquid paraffin, sorbitan monolaurate, monostearin, triethyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, poloxamer, and polyoxyethylene hydrogenated castor oil.

[0035] Examples of binders, fluidizing agents or lubricants (anti-adhesion agents), coloring agents, and sweetening agents are as described above, and may include those exemplified as additives for granules.

[0036] The lower limit of the coating layer content may be 1 part by weight or more, 2 parts by weight or more, or 3 parts by weight or more, based on 100 parts by weight of the granules. The upper limit of the coating layer content may be 100 parts by weight or less, 70 parts by weight or less, 60 parts by weight or less, or 40 parts by weight or less, based on 100 parts by weight of the granules. If the content is within the above range, the water penetration rate can be appropriately adjusted, allowing for an appropriate lag time.

[0037] 1.2 Granule structure and properties The granules may or may not have an internal structure. In one embodiment, the granules have a layered structure. In this embodiment, vonoprazan fumarate and aspartic acid may be contained in the same layer or in different layers. It is preferred that the carbonate be contained in a layer different from vonoprazan fumarate and aspartic acid.

[0038] The granules may comprise a vonoprazan fumarate-containing core, an intermediate layer, and a coating layer. The granules may further comprise a separating layer. These layers may be arranged in the following order from the center of the granule towards the outer shell: vonoprazan fumarate-containing core, separating layer (optional), intermediate layer, and coating layer.

[0039] The vonoprazan fumarate-containing core contains vonoprazan fumarate and is the central region of the granule. In one embodiment, the vonoprazan fumarate-containing core contains aspartic acid.

[0040] The separating layer is a layer that separates the vonoprazan fumarate-containing core from the intermediate layer, and the provision of the separating layer prevents an unexpected reaction between the vonoprazan fumarate contained in the vonoprazan fumarate-containing core and the carbonate contained in the intermediate layer due to contact therebetween.

[0041] The intermediate layer is a layer located outer than the vonoprazan fumarate-containing core. In one embodiment, the intermediate layer contains a carbonate. With this configuration, the vonoprazan fumarate-containing core and the carbonate-containing intermediate layer are different layers, so that water can be used in the production of the vonoprazan fumarate-containing core (using water in the formation of the carbonate-containing layer may result in foaming due to a reaction between the carbonate and water).

[0042] The coating layer is located on the outer shell of the granule and prevents moisture and other contaminants from penetrating into the interior of the granule.

[0043] The granules may have layers other than those mentioned above, and the layers mentioned above may also include further internal structures.

[0044] The layers described above or other layers may contain other components, such as additives.

[0045] The vonoprazan fumarate-containing core may contain a disintegrant. Examples of the disintegrant are as described above. The content of the disintegrant in the vonoprazan fumarate-containing core may be 0.5 to 50% by weight, assuming that the weight of the granule is 100% by weight.

[0046] The intermediate layer and / or the separating layer may contain a binder. This configuration facilitates layer formation. Examples of binders are as described above. The binder content in the granules may be 0.1 to 20% by weight, assuming the weight of the granules to be 100% by weight.

[0047] The intermediate layer and / or the separating layer may contain a fluidizing agent or a lubricant (anti-adhesion agent). This configuration suppresses the electrostatic charge of the particles, making the manufacturing process smoother. The content of the fluidizing agent or lubricant in the granules may be 0.01 to 50% by weight, assuming the weight of the granules to be 100% by weight.

[0048] The shape of the granules varies depending on the granulation method and is not particularly limited, but examples include spherical, cylindrical, and oblong (elliptical) shapes.

[0049] Granule D 50 The lower limit of the D of the granules can be 50 μm or more or 100 μm or more. 50 The upper limit of D may be 1000 μm or less or 800 μm or less. 50 is calculated from the particle size distribution obtained according to the particle size measurement method by laser diffraction in the particle size measurement method of the Japanese Pharmacopoeia, 17th Edition.

[0050] [2. Solid Preparations] One embodiment of the present invention is a solid formulation containing vonoprazan fumarate, carbonate, and aspartic acid. These three components may or may not be contained in the granules described in Section [1]. It is believed that the combination of the three components has the effect of reducing dissolution delay after storage, so it is not necessary for the three components to be contained in the granules to achieve this effect.

[0051] Examples of specific forms of solid preparations include tablets (such as orally disintegrating tablets), granules, fine granules, and powders. Granules and other optional ingredients may also be filled into a capsule base to form capsules (such as hard capsules and soft capsules).

[0052] The solid dosage form contains vonoprazan fumarate, carbonate, and aspartic acid as described in Section [1]. The description in [1] also applies to other ingredients that the solid dosage form may contain.

[0053] In a solid formulation, the lower limit of the granule content may be 1% by weight or more, 5% by weight or more, or 10% by weight or more, based on 100% by weight of the solid formulation, and the upper limit of the granule content may be 90% by weight or less, 80% by weight or less, 70% by weight or less, or 60% by weight or less, based on 100% by weight of the solid formulation.

[0054] In one embodiment, the granule or solid formulation contains an antioxidant and / or titanium oxide, which can reduce the production and increase of nitroso forms.

[0055] Examples of antioxidants include dibutylhydroxytoluene, propyl gallate, ascorbic acid, α-tocopherol, glycine, lysine, histidine, arginine, L-cysteine, sodium carbonate, and aminobenzoic acid. Among these, dibutylhydroxytoluene and / or propyl gallate are preferred, and propyl gallate is more preferred.

[0056] For the purpose of suppressing an increase in nitroso forms, the location where the antioxidant and / or titanium oxide is incorporated in the granule or solid preparation is not particularly limited, and examples of the location include the vonoprazan fumarate-containing core, the coating of the vonoprazan fumarate-containing core, the tablet powder, and the film coating of the tablet.

[0057] The content of the antioxidant and / or titanium oxide can be adjusted as appropriate. For example, the content of the antioxidant and / or titanium oxide can be 0.1% by weight or more and less than 15% by weight, where the total weight of the solid preparation is 100% by weight.

[0058] The solid preparation may be packaged as needed using PTP (Press Through Pack) packaging, bottle filling, aluminum packaging, etc. Examples of materials constituting PTP packaging include resins (polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, polycarbonate, etc.) and metals (aluminum, etc.). These materials may be used alone or in combination of two or more. Examples of combinations include a laminated film of polyvinyl chloride and polyvinylidene chloride, and a laminated film of polyvinyl chloride and polychlorotrifluoroethylene. The above-mentioned resins can be molded into a resin sheet with pockets, and the solid preparations can be placed in the pockets, followed by sealing with aluminum foil to form PTP packaging.

[0059] The PTP package containing the solid formulation may be further packaged in an aluminum pillow. This aluminum pillow may further contain a desiccant. Examples of desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite.

[0060] To improve identification, the surface of a solid dosage form may be engraved or printed with information such as the product number, name of the active ingredient, the content of the active ingredient, dosage form, product number, QR code, or barcode. Engraving or printing can be done directly on the surface of plain or film-coated tablets. Examples of printing methods include ink printing (plate-type transfer printing, gravure printing, offset printing, inkjet printing, etc.) and laser printing. The ink used for printing can be selected from edible inks containing dyes and / or pigments. The ink may be one color, or two or more colors may be used to improve identification.

[0061] 3. Manufacturing Methods of Granules and Solid Preparations One aspect of the present invention is a method for producing granules. This method includes a step of granulating raw materials containing vonoprazan fumarate, carbonate, and aspartic acid into granules. Specific methods for producing granules can be any known methods.

[0062] For example, the vonoprazan fumarate-containing cores can be produced by wet granulation or dry granulation. If necessary, further steps such as drying and granulation may be included. Examples of wet granulation include fluidized bed granulation, stirring granulation, rolling granulation, extrusion granulation, wet crushing granulation, kneading granulation, continuous direct granulation, and hybrid fluidized bed granulation. Examples of dry granulation include dry hybrid granulation, flake granulation, briquette granulation, and melt granulation.

[0063] For example, the outer layer (separating layer, intermediate layer, coating layer, etc.) of the vonoprazan fumarate-containing core can be formed using an apparatus such as a fluidized bed coater, a Wurster fluidized bed coater, a centrifugal fluidized bed coater, or a tumbling fluidized bed coater.

[0064] One aspect of the present invention is a method for producing a solid preparation. This production method includes a step of molding raw materials containing vonoprazan fumarate, carbonate, and aspartic acid. A conventionally known molding method can be used as the specific molding method. For example, tablets can be produced by molding raw materials containing vonoprazan fumarate, carbonate, and aspartic acid by tableting.

[0065] In the method for producing a solid preparation, vonoprazan fumarate, carbonate, and aspartic acid may be contained in the form of granules or in other forms.

[0066] The materials that can be used in the production of granules and solid preparations are as explained in Section [1], so they will not be described again.

[0067] 4. Method for reducing delay in dissolution of vonoprazan fumarate after storage One aspect of the present invention is a method for reducing delay in dissolution of vonoprazan fumarate from granules after storage, the method comprising the step of granulating raw materials containing vonoprazan fumarate, carbonate, and aspartic acid into granules.

[0068] One aspect of the present invention is a method for reducing the delayed dissolution of vonoprazan fumarate from a solid formulation after storage. This production method includes a step of molding a raw material containing vonoprazan fumarate, a carbonate, and aspartic acid. For example, molding the raw material containing vonoprazan fumarate, a carbonate, and aspartic acid by tableting results in a method for reducing the delayed dissolution of vonoprazan fumarate from tablets after storage.

[0069] Materials that can be used in the manufacture of granules and solid dosage forms are as explained in Section [1], so they will not be described again. Methods that can be used in the manufacture of granules and solid dosage forms are as explained in Section [2], so they will not be described again. [Example]

[0070] [Test method] The dissolution test was carried out in accordance with Japanese Pharmacopoeia Dissolution Test Method 2. The specific test conditions are as follows: Paddle rotation speed: 50 rotations per minute Test solution: pH 6.8 phosphate buffer solution (Japanese Pharmacopoeia Disintegration Test Method No. 2 solution) Test solution volume: 900 mL Measurement equipment: Fiber probe type UV-visible spectrophotometer (Rainbow, Pion Inc.) ·Measurement wavelength: 267nm Measurements: 3 times (the average of the 3 measurements was used as the dissolution rate)

[0071] In this example, changes in the dissolution behavior of a drug after storage were investigated. As a whole, dissolution tests were carried out at the following four time points, and the dissolution behaviors were compared. Immediately after production After one month of storage at 25°C, 75% RH, and open conditions After 3 months of storage at 25°C, 75% RH, and open conditions After 2 weeks of storage at 40°C, 75% RH, and open conditions

[0072] 〔material〕 The materials used in the Reference Examples, Examples and Comparative Examples are as follows. ◆Drug-containing granules Vonoprazan fumarate-containing core Vonoprazan fumarate 1 (milled at 18,000 rpm) Vonoprazan fumarate 2 (milled at 9000 rpm) Low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu Chemical Co., Ltd.) Hydroxypropyl cellulose (HPC-L FP, Nippon Soda Co., Ltd.) Corn starch (Cornstarch (W), Nihon Shokuhin Kako Co., Ltd.) D-mannitol (PEARLITOL 50C, Rockete) Aspartic acid (Fujifilm Wako Pure Chemical Industries, Ltd.) ●Separation layer Talc (Talc Hayashi, Hayashi Kasei Co., Ltd.) Hydroxypropyl cellulose (HPC-SL, Nippon Soda Co., Ltd.) ●Middle class Sodium bicarbonate (AGC Co., Ltd.) Talc (Talc Hayashi, Hayashi Kasei Co., Ltd.) Hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) Coating layer Aminoalkyl methacrylate copolymer E (Eudragit E, Evonik Nutrition & care GmbH) Talc (Talc Hayashi, Hayashi Kasei Co., Ltd.) Titanium oxide (Freund Corporation) Fast-disintegrating granules D-mannitol Ethyl cellulose Crystalline cellulose Light anhydrous silica Corn starch Crospovidone ◆Others Light anhydrous silicic acid (Adsolider-101, Freund Corporation) Aspartame Peppermint Micron Magnesium stearate

[0073] [Reference Examples 1 and 2, Example 1, Comparative Example 1] Orally disintegrating tablets containing vonoprazan fumarate as the active ingredient were prepared according to the following procedure. The amounts of the ingredients used in each step are shown in Table 1a or Table 1b (unit: mg). (Preparation of Vonoprazan Fumarate-Containing Core) 1. The materials listed in the section on vonoprazan fumarate-containing cores in Table 1a were charged into a stirring mixer granulator and mixed. L-aspartic acid was pulverized before being charged into the device. 2. The raw materials were granulated by spraying purified water while stirring. 3. The particles that passed through a 30 mesh (opening: 500 μm) sieve but did not pass through a 200 mesh (opening: 75 μm) sieve were used as vonoprazan fumarate-containing cores. The particle size distribution of the vonoprazan fumarate-containing cores was D 50 The target was 150 to 190 μm. (Formation of separation layer) 4. Hydroxypropyl cellulose was dissolved in absolute ethanol. 5. Talc was added to the resulting solution and stirred to obtain coating solution (1). 6. The vonoprazan fumarate-containing cores were placed in a tumbling fluidized bed coating device and sprayed with the coating solution (1), thus forming a separation layer. (Formation of intermediate layer) 7. Hydroxypropyl cellulose was dissolved in absolute ethanol. 8. Talc and sodium bicarbonate were added to the resulting solution and stirred to obtain coating solution (2). 9. The particles on which the separation layer was formed were placed in a tumbling fluidized bed coating device, and the coating liquid (2) was sprayed onto the particles, thus forming an intermediate layer. (Formation of coating layer) 10. Aminoalkyl methacrylate copolymer E was dissolved in a mixture of absolute ethanol and purified water. 11. Titanium oxide was added to the solution and mixed. Titanium oxide was added in a dispersed state in a mixture of absolute ethanol and purified water. 12. Talc was added to the resulting mixture to obtain coating solution (3). 13. The particles with the intermediate layer formed were placed in a tumbling fluidized bed coating device and sprayed with coating solution (3). In this way, drug-containing granules were obtained. The particle size distribution of the drug-containing granules was D 50 The target was 200 to 240 μm. (Preparation of Rapidly Disintegrating Granules) 14. The ingredients and purified water listed in Table 1b were granulated in a fluidized bed granulator to prepare rapidly disintegrating granules. (Preparation of Orally Disintegrating Tablets) 15. The ingredients listed in the tableting powder in Table 1a, except for magnesium stearate, were mixed with the drug-containing granules. 16. Magnesium stearate was further added and mixed. 17. The resulting mixture was placed in a single punch tablet press (HANDTAB-200, Ichihashi Seiki Co., Ltd.) and compressed into tablets using a 9.0 mm punch to prepare orally disintegrating tablets.

[0074] The measured particle size distribution in Example 1 was as follows: 50 was calculated from the particle size distribution obtained according to the particle size measurement method by laser diffraction in the particle size measurement method of the 17th edition of the Japanese Pharmacopoeia. The particle size distribution measurement device actually used was a Mastersizer 3000 (Malvern Panalytical). D of vonoprazan fumarate in step 1 50 :12.3μm D of the vonoprazan fumarate-containing core in step 3 50 :171μm D of drug-containing granules in step 13 50 :219μm

[0075] The thickness of the orally disintegrating tablets obtained in Example 2 was 3.93 mm, and that of Comparative Example 1 was 3.89 mm.

[0076] [Table 1] JPEG2026027795000003.jpg42150

[0077] [result] The results of a comparison between Reference Examples 1 and 2 and Example 1 are shown in Figure 1. In this comparison, the dissolution behaviors were compared at the following three time points. Immediately after production After one month of storage at 25°C, 75% RH, and open conditions After 3 months of storage at 25°C, 75% RH, and open conditions

[0078] Reference Example 1 corresponds to the formulation described in Table 12 of Patent Document 1, and Reference Example 2 is a formulation in which the amount of carbonate added is increased in Reference Example 1. None of Reference Examples 1 and 2 contains aspartic acid. As can be seen from FIG. 1, when the amount of carbonate added is increased in a formulation that does not contain aspartic acid, a significant delay in dissolution after storage was observed. However, by adding aspartic acid, the delay in dissolution after storage was reduced even in a formulation that contained the same amount of carbonate as Reference Example 2 (see Reference Example 2 and Example 1).

[0079] The results of the comparison between Example 1 and Comparative Example 1 are shown in Figure 2. In this comparison, the dissolution behavior was compared at the following two time points. Immediately after production After 2 weeks of storage at 40°C, 75% RH, and open conditions

[0080] As can be seen from Figure 2, the addition of aspartic acid reduced the delay in dissolution after storage. The degree of pulverization of vonoprazan fumarate differs between Reference Examples 1 and 2 and Example 1, and the dissolution properties of the orally disintegrating tablet of Comparative Example 1 were investigated to examine the effect of this difference on the dissolution behavior. As is clear from the results in Figure 2, the reduction in delay in dissolution after storage is due not to the degree of pulverization of vonoprazan fumarate, but to the presence or absence of the inclusion of aspartic acid. [Industrial Applicability]

[0081] The present invention can be used for medicines containing vonoprazan fumarate.

Claims

1. Contains vonoprazan fumarate, carbonate, and aspartic acid, Granules.

2. the carbonate is one or more selected from the group consisting of potassium carbonate, precipitated calcium carbonate, sodium bicarbonate, dry sodium carbonate, sodium carbonate hydrate, and magnesium carbonate; The granules according to claim 1.

3. The granules each include, in this order from the center to the outer shell, a vonoprazan fumarate-containing core, an intermediate layer, and a coating layer. The granules according to claim 1.

4. a separating layer is further provided between the vonoprazan fumarate-containing core and the intermediate layer. The granules according to claim 3.

5. the aspartic acid is contained in the vonoprazan fumarate-containing core; The carbonate is contained in the intermediate layer. The granules according to claim 3.

6. When the content of the vonoprazan fumarate is 100% by weight, the content of the carbonate is 30% by weight or more. The granules according to claim 1.

7. When the content of the carbonate is 100% by weight, the content of the aspartic acid is 15% by weight or more. The granules according to claim 1.

8. The granules according to any one of claims 1 to 7 are contained. Solid dosage forms.

9. The solid formulation according to claim 8, which is a tablet.

10. Contains vonoprazan fumarate, carbonate, and aspartic acid, Solid dosage forms.

11. granulating raw materials containing vonoprazan fumarate, carbonate, and aspartic acid into granules; Method for manufacturing granules.

12. granulating raw materials containing vonoprazan fumarate, carbonate, and aspartic acid into granules; A method for reducing the delay in dissolution of vonoprazan fumarate from a granule or solid dosage form after storage.

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