Vonoprazan-containing orally disintegrating tablets

Abstract

The objective is to provide an orally disintegrating tablet containing vonoprazan fumarate that is miniaturized, has excellent photostability and bitterness masking properties, and possesses good tablet hardness and good disintegration properties. [Solution] The present invention provides an orally disintegrating tablet comprising granules containing vonoprazan fumarate and a low-melting-point substance with a freezing point of 60°C or lower, and a pharmaceutical excipient.

Description

Technical Field

[0001] The present invention relates to an orally disintegrating tablet containing vonoprazan fumarate, which is excellent in light stability and bitterness masking property and has good tablet hardness and good disintegration property.

Background Art

[0002] Vonoprazan inhibits proton pump (H+ / K+-ATPase) activity in a reversible and K+-antagonistic inhibitory mode, and as a result, suppresses acid secretion. Therefore, it is sometimes called a potassium-competitive acid blocker (P-CAB) or an acid pump antagonist (ACPA or APA), and is useful for the treatment of peptic ulcers (for example, gastric ulcer, gastric ulcer due to postoperative stress, duodenal ulcer, anastomotic ulcer, ulcer caused by non-steroidal anti-inflammatory drugs, ulcer due to postoperative stress, etc.) (Patent Document 1).

[0003] "Takecab (registered trademark) tablets" and "Takecab (registered trademark) OD tablets", which contain vonoprazan as an active ingredient, are sold as pharmaceutical preparations (Takeda Pharmaceutical Company Limited) (Non-Patent Document 1, Non-Patent Document 2).

[0004] Patent Document 2 describes a preparation containing fine granules or granules having a core granule containing an organic acid salt of vonoprazan, an intermediate layer containing an organic acid or its salt, and a coating layer containing a water-insoluble polymer.

[0005] However, there is no description of a miniaturized orally disintegrating tablet containing granules containing vonoprazan fumarate and a low melting point substance having a freezing point of 60°C or lower.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

[0007] [Non-Patent Document 1] Package insert for "Takecab Tablets 10mg / 20mg," revised September 2024 (5th edition) [Non-Patent Document 2] Package insert for "Takecab OD Tablets 10mg / 20mg," revised September 2024 (4th edition) [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention is to provide an orally disintegrating tablet containing vonoprazan fumarate that is miniaturized, has excellent photostability and bitterness masking properties, and possesses good tablet hardness and good disintegration properties. [Means for solving the problem]

[0009] As a result of diligent research, the inventors of the present invention have discovered that by containing a low-melting-point substance with a freezing point of 60°C or lower and coating it with a specific coating agent, it is possible to provide an orally disintegrating tablet that is miniaturized, has excellent light stability and bitterness masking properties, and possesses good tablet hardness and good disintegration properties, thus completing the present invention.

[0010] In other words, the present invention is (1) Orally disintegrating tablets containing granules containing vonoprazan fumarate and a low melting point substance with a freezing point of 60°C or less, and a pharmaceutical excipient. (2) The granules are orally disintegrating tablets as described in (1) above, containing fumaric acid or a salt thereof. (3) Orally disintegrating tablets according to (1) and (2) above, wherein the granules are coated with one or more coating agents selected from hydrophilic additives and water-insoluble polymers. (4) The orally disintegrating tablet according to (1) above, wherein the granules contain one or more coloring agents selected from the group consisting of ferric oxide, yellow ferric oxide, black iron oxide, titanium dioxide, talc, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, and food blue No. 3. (5) The orally disintegrating tablet according to (1) above, wherein the low melting point substance with a freezing point of 60°C or less is one or more selected from the group consisting of macrogol, monoglyceryl stearate, cetanol, and polyoxyl stearate 40. (6) The orally disintegrating tablet according to (3) above, wherein the water-insoluble polymer is one or more selected from the group consisting of ethylcellulose, methacrylate copolymer LD, aminoalkyl methacrylate copolymer E, ammoniaalkyl methacrylate copolymer, hypromellose acetate succinate, and hypromellose phthalate. (7) The orally disintegrating tablet according to (3) above, wherein the hydrophilic additive is one or more selected from the group consisting of D-mannitol, lactose monohydrate, isomalt, hydroxypropylcellulose, hypromellose, methylcellulose, povidone, and polyvinyl alcohol (partially hydrolyzed). (8) Orally disintegrating tablets according to (1) above, comprising one or more selected from the group consisting of excipients, disintegrants, sweeteners, fluidizers, and lubricants. (9) The orally disintegrating tablet according to (8) above, wherein the excipient is one or more selected from the group consisting of D-mannitol, lactose monohydrate, isomalt, erythritol, trehalose, crystalline cellulose, and corn starch. (10) The orally disintegrating tablet according to (8) above, wherein the disintegrant is one or more selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, croscarmellose calcium, and croscarmellose starch sodium. (11) The orally disintegrating tablet according to (8) above, wherein the sweetener is one or more selected from the group consisting of sucralose, aspartame, acesulfame potassium, and thaumatin. (12) The orally disintegrating tablet according to (8) above, wherein the fluidizing agent is one or more selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, and talc. (13) The orally disintegrating tablet according to (8) above, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and hydrogenated oil. (14) The orally disintegrating tablet described in (1) above, which contains 10% by weight or more of granules per tablet. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a vonoprazan-containing orally disintegrating tablet that is miniaturized, has excellent photostability and bitterness masking properties, and possesses good tablet hardness and good disintegration properties. [Modes for carrying out the invention]

[0012] In this specification, "miniaturization" means a higher proportion of vonoprazan fumarate per tablet than commercially available orally disintegrating tablets containing vonoprazan fumarate. For example, the proportion per tablet may be 10-40% by weight in one embodiment, 15-40% by weight in another embodiment, or 20-40% by weight in another embodiment.

[0013] In this specification, "photostabilization" means suppressing the increase in the amount of related substances and / or the generation and increase of unknown substances caused by the decomposition of vonoprazan fumarate after light irradiation. As an evaluation method, for example, the photostability of the tablets is evaluated by storing the tablets under harsh light conditions, then testing them by high-performance liquid chromatography (HPLC), calculating the amount of related substances, and comparing it with the total amount of related substances at the start of the test. For example, under irradiation conditions of 3000 Lux·hr, the tablets can be evaluated as stabilized against light if, in one embodiment, the total amount of related substances at a total irradiation dose of 600,000 Lux·hr is 0.4% or less, and in another embodiment, the total amount of related substances at a total irradiation dose of 1,200,000 Lux·hr is 0.6% or less.

[0014] As used herein, "excellent bitterness masking property" means that the dissolution amount of the active ingredient during the period from being placed in the mouth until disintegration (within 30 seconds) is suppressed. For example, when the test is conducted by the upright and inverted syringe method, the dissolution amount of bonoprazan in 5 ml of water at 37°C is defined as 20% or less, 10% or less, or 5% or less within 30 seconds in certain embodiments.

[0015] As used herein, "upright and inverted syringe method" refers to using a simple dissolution test method (upright and inverted syringe method) that mimics the oral cavity. By this method, the dissolution amount of the drug can be measured, and the masking evaluation of bitterness can be performed by comparing it with the threshold for feeling the bitterness of the drug (Reference: Yasuhiko Nakamura et al., Particle Design and Pharmaceutical Technology, 121 - 128 (1993)).

[0016] As used herein, "good tablet hardness" means having a tablet hardness such that cracking or chipping does not occur when the tablet is taken out from the PTP package. For example, an orally disintegrating tablet having a hardness of 30 N or more, 40 N or more, or 50 N or more in certain embodiments is defined.

[0017] As used herein, "good disintegrating property" is a property of a compression molded product that has rapid disintegration when placed in the mouth or in water. Specifically, (a) in the disintegration test using the disintegration test apparatus of the 17th revised Japanese Pharmacopoeia, a tablet that disintegrates within 60 seconds or within 45 seconds in certain embodiments, and / or (b) in the disintegration test using an orally disintegrating tablet measuring device (TRICOP TESTER (registered trademark); Okada Seiko Co., Ltd.), a tablet that disintegrates within 60 seconds or within 45 seconds in certain embodiments can be said to be an orally disintegrating tablet that satisfies the conditions of good disintegrating property. The orally disintegrating tablet that satisfies the conditions of good disintegrating property according to the present invention is a tablet that corresponds to one or more of (a) to (b), and in certain embodiments, a tablet that corresponds to all of (a) to (b).

[0018] The bonoprazan-containing orally disintegrating tablet of the present invention will be described below.

[0019] The vonoprazan used in this invention is chemically named 1-[5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-yl]-N-methylmethanamine, and vonoprazan fumarate in particular is already used clinically as a pharmaceutical and is readily available. Vonoprazan fumarate can be used in either a crystalline or amorphous state.

[0020] The indications and effects are gastric ulcer, duodenal ulcer, reflux esophagitis, prevention of recurrence of gastric or duodenal ulcers during low-dose aspirin administration, prevention of recurrence of gastric or duodenal ulcers during nonsteroidal anti-inflammatory drug administration, and adjunct to eradication of Helicobacter pylori in (gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, stomach after endoscopic treatment for early gastric cancer, and Helicobacter pylori-associated gastritis).

[0021] The amount of vonoprazan used is not particularly limited, as long as it is in the amount of vonoprazan. For example, as vonoprazan fumarate, the amount in the granules may be 40-95% by weight or 50-90% by weight in one embodiment.

[0022] The low-melting-point substances with a freezing point of 60°C or less used in the present invention are not particularly limited as long as they achieve the objectives of the present invention. Examples of such substances include glyceryl monostearate, macrogol 4000, macrogol 6000, cetanol, stearyl alcohol, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 60, polysorbate 60, lauromacrogol, etc. Examples of such substances include macrogol, monoglyceryl stearate, cetanol, and polyoxyl stearate 40. These low-melting-point substances can be used individually or in combination of two or more. The amount blended is 1 to 50% by weight in some embodiments, 5 to 40% by weight in some embodiments, and 10 to 30% by weight in some embodiments, in the granules.

[0023] Vonoprazan-containing granules can be coated with a coating agent containing hydrophilic additives and water-soluble polymers.

[0024] The hydrophilic additive used in the present invention is not particularly limited as long as it achieves the objective of the present invention. Examples of such additives include sugars, sugar alcohols, and water-soluble polymers. Examples of such sugars include lactose monohydrate, refined sucrose, and trehalose. Examples of such sugar alcohols include D-mannitol, erythritol, xylitol, and maltitol. Examples of such water-soluble polymers include hydroxypropyl cellulose, hypromellose, methylcellulose, povidone, and polyvinyl alcohol (partially hydrated). These additives can be used individually or in combination of two or more. The amount added to the coating layer is, in some cases, 1 to 50% by weight, in other cases, 5 to 40% by weight, and in other cases, 10 to 30% by weight.

[0025] Vonoprazan-containing granules can be coated with a coating agent containing a water-insoluble polymer. The water-insoluble polymer used in the present invention is not particularly limited as long as it achieves the objectives of the present invention. Examples of gastric-soluble polymers include enteric-coated polymers and pH-independent polymers. Examples of gastric-soluble polymers include aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate. Examples of enteric-coated polymers include methacrylic acid copolymer LD, hypromellose acetate succinate, and hypromellose phthalate. Examples of pH-independent polymers include ethylcellulose, ammoniaalkyl methacrylate copolymer, and ethyl acrylate / methyl methacrylate copolymer dispersions. The polymers can be used individually or in combination of two or more. The amount blended in the coating layer is 50-99% by weight in one embodiment, 60-95% by weight in another embodiment, and 70-90% by weight in another embodiment.

[0026] Vonoprazan-containing granules may optionally contain organic acids.

[0027] The organic acid used in the present invention is not particularly limited as long as it achieves the objective of the present invention. For example, fumaric acid or a salt thereof can be used. In one embodiment, sodium fumarate can be used.

[0028] The vonoprazan-containing granules may optionally be coated with a coating agent containing a coloring agent.

[0029] The coloring agents used in the present invention are not particularly limited as long as they achieve the objectives of the present invention. Examples of coloring agents include ferric oxide, yellow ferric oxide, black iron oxide, titanium dioxide, talc, Yellow No. 4, Yellow No. 5, Red No. 3, Red No. 102, Blue No. 3, etc., and examples of coloring agents include titanium dioxide, ferric oxide, yellow ferric oxide, etc. One or more coloring agents can be used in combination. The amount of coloring agent in the orally disintegrating tablet is 0.001 to 1% by weight in one embodiment, 0.01 to 0.5% by weight in another embodiment, and 0.01 to 0.3% by weight in another embodiment.

[0030] The pharmaceutical additives used in the present invention are not particularly limited as long as they achieve the objectives of the present invention. Examples include excipients, disintegrants, sweeteners, fluidizers, lubricants, and the like.

[0031] Examples of excipients include D-mannitol, low-substituted hydroxypropylcellulose, polyvinyl alcohol (fully hydrolyzed) granules, D-mannitol, lactose monohydrate, isomalt, erythritol, trehalose, crystalline cellulose, and corn starch. Excipients can be used individually or in combination of two or more.

[0032] Examples of disintegrants include crospovidone, low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, croscarmellose calcium, and croscarmellose starch sodium. One or more disintegrants can be used in combination.

[0033] Examples of sweeteners include sucralose, aspartame, acesulfame potassium, and thaumatin. One or more sweeteners can be used in combination.

[0034] Examples of fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, and talc.

[0035] Examples of lubricants include magnesium stearate, sodium stearyl fumarate, and hydrogenated oil.

[0036] Other examples of pharmaceutical excipients include binders, surfactants, foaming agents, and fragrances.

[0037] Examples of binders include hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, gum arabic, and hydroxyethyl cellulose.

[0038] Examples of surfactants include polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil.

[0039] Examples of foaming agents include baking soda.

[0040] Examples of flavorings include lemon, lemon-lime, orange, and menthol.

[0041] The amount used is not particularly limited, as long as it does not affect the achievement of the desired effects of the present invention.

[0042] The vonoprazan-containing granules used in the present invention can be manufactured by known methods, including steps such as crushing, mixing, granulation, and drying. Specifically, the vonoprazan-containing granules used in the present invention can be obtained by melt granulation of vonoprazan (which may be pre-crushed) and a low-melting-point substance. A coating agent is sprayed onto the manufactured granules to produce coated granules.

[0043] The orally disintegrating tablets of the present invention are manufactured by mixing granules or coated granules containing vonoprazan fumarate with excipients (e.g., D-mannitol, low-substituted hydroxypropylcellulose, polyvinyl alcohol (fully hydrolyzed) granules, etc.), disintegrants (e.g., crospovidone, etc.), sweeteners (e.g., sucralose, etc.), fluidizers (e.g., light anhydrous silicic acid, etc.), and lubricants (e.g., magnesium stearate, etc.), and then compressing the mixture (e.g., by tableting). Furthermore, film-coated orally disintegrating tablets are produced by coating the orally disintegrating tablets with a coating agent (e.g., hypromellose, etc.). [Examples]

[0044] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way to the following examples. [Examples]

[0045] 40.08 g of vonoprazan fumarate and 6.42 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a rolling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a 500 μm screen sieve. 3.1 g of the sized granules were mixed with 17.58 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEXQ-100), 1.1 g of crospovidone (BASF Co., Ltd.: Kollidon CL-F), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: Magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0046] 40.08 g of vonoprazan fumarate and 6.42 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a rolling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 850 μm. 3.1 g of the sized granules were mixed with 17.14 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1 g of crospovidone (BASF: Kollidon CL-F), 0.22 g of aspartame (Ajinomoto Co., Ltd.), 0.22 g of acesulfame potassium (Maruzen Pharmaceutical Co., Ltd.), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: Magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0047] 26.72g of vonoprazan fumarate, 20g of sodium fumarate (manufactured by Fuso Chemical Industry Co., Ltd.), and 4.28g of glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a rolling fluidized bed granulation dryer (manufactured by Powrec: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. 2.55g of the sized granules were mixed with 7.79g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (manufactured by Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 0.55g of crospovidone (manufactured by BASF: Kollidon CL-F), and 0.11g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.: plant-derived magnesium stearate). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0048] 26.72 g of vonoprazan fumarate, 20 g of sodium fumarate (manufactured by Fuso Chemical Industry Co., Ltd.), and 4.28 g of glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a tumbling fluidized bed granulator (manufactured by Powrec: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. A mixture of 2.55g of whole granules, 7.57g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 0.55g of crospovidone (BASF: Kollidon CL-F), 0.11g of aspartame (Ajinomoto Co., Ltd.), 0.11g of acesulfame potassium (Maruzen Pharmaceutical Co., Ltd.), and 0.11g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived) was prepared. By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained.

[0049] ≪Comparative Example 1≫ 6.7g of vonoprazan fumarate was mixed with 42.8g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully hydrolyzed) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 4.4g of crospovidone (BASF: Kollidon CL-F), and 1.1g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed powder obtained above and compressing it with a rotary tablet press (Kikusui Seisakusho: VEL5), an orally disintegrating tablet of the comparative example with a diameter of 8 mm and a mass of 0.22 g was obtained.

[0050] ≪Comparative Example 2≫ 200.4 g of vonoprazan fumarate was granulated in a fluid-bed granulator (Pawrec MP-01) using a binding solution prepared by dissolving 11.1 g of hypromellose (Shin-Etsu Chemical Co., Ltd.: TC-5E) in 210.9 g of purified water. The resulting granules were sized using a sieve with a screen diameter of 500 μm. The resulting granules were then sized using a sieve with a screen diameter of 850 μm. 2.82 g of the sized granules were mixed with 17.86 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1 g of crospovidone (BASF: Kollidon CL-F), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), an orally disintegrating tablet of the comparative example with a diameter of 8 mm and a mass of 0.22 g was obtained.

[0051] Table 1 shows the formulations for Examples 1-4 and Comparative Examples 1-2.

[0052] [Table 1] [Examples]

[0053] 40.08 g of vonoprazan fumarate and 6.42 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a tumbling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. Separately, a coating solution was prepared using 0.9 g of ammoniaalkyl methacrylate copolymer dispersion type B (EVONIK: Eudragit RS30D), 0.075 g of ammoniaalkyl methacrylate copolymer dispersion type A (EVONIK: Eudragit RL30D), 0.125 g of triethyl citrate (Morimura Shoji: Citroflex (SC-60)), 0.125 g of glyceryl monostearate (Riken Vitamin: Glyceryl Monostearate P-100), 0.05 g of polysorbate (Sanyo Chemical Industries: Polysorbate 80), 0.5 g of succinic acid (Fuso Chemical Industries), and 2.825 g of purified water. 15.5 g of granular material was placed in a tumbling fluidized bed granulator (Powrec: FD-MP-micro), and the coating solution was sprayed to perform granular coating. The obtained granules were sized using a sieve with a screen diameter of 850 μm. 3.455 g of the sized coated granules were mixed with 17.225 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1 g of crospovidone (BASF: Kollidon CL-F), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0054] 40.08 g of vonoprazan fumarate and 6.42 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a tumbling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. Separately, a coating solution was prepared using 0.9g of ammoniaalkyl methacrylate copolymer dispersion type B (EVONIK: Eudragit RS30D), 0.075g of ammoniaalkyl methacrylate copolymer dispersion type A (EVONIK: Eudragit RL30D), 0.125g of triethyl citrate (Morimura Shoji: Citroflex (SC-60)), 0.125g of glyceryl monostearate (Riken Vitamin: Glyceryl Monostearate P-100), 0.05g of polysorbate (Sanyo Chemical Industries: Polysorbate 80), 0.5g of succinic acid (Fuso Chemical Industries), and 2.825g of purified water. 15.5g of granular material was then placed in a tumbling fluidized bed granulator (Powrec: FD-MP-micro) and the coating was carried out. The obtained granules were sized using a sieve with a screen diameter of 850 μm. 3.455 g of the sized coated granules were mixed with 17.225 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1 g of crospovidone (BASF: Kollidon CL-F), 0.22 g of aspartame (Ajinomoto Co., Ltd.), 0.22 g of acesulfame potassium (Maruzen Pharmaceutical Co., Ltd.), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0055] 40.08 g of vonoprazan fumarate and 6.42 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a tumbling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. Separately, a coating solution was prepared using 6g of ammoniaalkyl methacrylate copolymer dispersion type B (EVONIK: Eudragit RS30D), 0.5g of ammoniaalkyl methacrylate copolymer dispersion type A (EVONIK: Eudragit RL30D), 0.25g of triethyl citrate (Morimura Shoji: Citroflex (SC-60)), 0.25g of glyceryl monostearate (Riken Vitamin: Glyceryl Monostearate P-100), 0.1g of polysorbate (Sanyo Chemical Industries: Polysorbate 80), 1g of succinic acid (Fuso Chemical Industries), 0.25g of titanium dioxide (Toho Titanium: NA-61), and 5.65g of purified water. 31.0g of granular material was then placed in a tumbling fluidized bed granulator (Powrec: FD-MP-micro) and the coating was carried out. The obtained granules were sized using a sieve with a screen diameter of 850 μm. 3.48 g of the sized coated granules were mixed with 17.2 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1 g of crospovidone (BASF: Kollidon CL-F), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0056] 26.72 g of vonoprazan fumarate, 20 g of sodium fumarate (manufactured by Fuso Chemical Industry Co., Ltd.), and 4.28 g of glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a tumbling fluidized bed granulator (manufactured by Powrec: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. Separately, a coating solution was prepared using 6.0g of ammoniaalkyl methacrylate copolymer dispersion type B (EVONIK: Eudragit RS30D), 0.5g of ammoniaalkyl methacrylate copolymer dispersion type A (EVONIK: Eudragit RL30d), 0.25g of triethyl citrate (Morimura Shoji: Citroflex (SC-60)), 0.25g of glyceryl monostearate (Riken Vitamin: Glyceryl Monostearate P-100), 0.1g of polysorbate (Sanyo Chemical Industries: Polysorbate 80), 1.0g of succinic acid (Fuso Chemical Industries), and 5.65g of purified water. 25.5g of granular material was then placed in a tumbling fluidized bed granulator (Pawrec: FD-MP-micro) and the coating was carried out. The obtained granules were sized using a sieve with a screen diameter of 850 μm. 2.91 g of the sized coated granules were mixed with 7.44 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 0.55 g of crospovidone (BASF: Kollidon CL-F), and 0.11 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0057] 26.72 g of vonoprazan fumarate, 20 g of sodium fumarate (manufactured by Fuso Chemical Industry Co., Ltd.), and 4.28 g of glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.: Rikemar S-100P) were mixed and melt-granulated using a tumbling fluidized bed granulator (manufactured by Powrec: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. Separately, a coating solution was prepared using 6.0g of ammoniaalkyl methacrylate copolymer dispersion type B (EVONIK: Eudragit RS30D), 0.5g of ammoniaalkyl methacrylate copolymer dispersion type A (EVONIK: Eudragit RL30D), 0.25g of triethyl citrate (Morimura Shoji: Citroflex (SC-60)), 0.25g of glyceryl monostearate (Riken Vitamin: Glyceryl Monostearate P-100), 0.1g of polysorbate (Sanyo Chemical Industries: Polysorbate 80), 1.0g of succinic acid (Fuso Chemical Industries), and 5.65g of purified water. 25.5g of granular material was then placed in a tumbling fluidized bed granulator (Powrec: FD-MP-micro) and the coating was carried out. The obtained granules were sized using a sieve with a screen diameter of 850 μm. 2.91 g of the sized coated granules were mixed with 7.22 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 0.55 g of crospovidone (BASF: Kollidon CL-F), 0.11 g of aspartame (Ajinomoto Co., Ltd.), 0.11 g of acesulfame potassium (Maruzen Pharmaceutical Co., Ltd.), and 0.11 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained.

[0058] ≪Comparative Example 3≫ 11.1 g of hypromellose (Shin-Etsu Chemical Co., Ltd.: TC-5E) was dissolved in 210.9 g of purified water to form a binding solution. 200.4 g of vonoprazan fumarate (JINGSHENG Co., Ltd.) was then granulated in a tumbling fluidized bed granulator (Pawrec Co., Ltd.: MP-01). The resulting granules were sized using a sieve with a screen diameter of 500 μm. The resulting granules were then sized using a sieve with a screen diameter of 850 μm. Separately, a coating solution was prepared using 6g of ammoniaalkyl methacrylate copolymer dispersion type B (EVONIK: Eudragit RS30D), 0.5g of ammoniaalkyl methacrylate copolymer dispersion type A (EVONIK: Eudragit RL30D), 0.25g of triethyl citrate (Morimura Shoji: Citroflex (SC-60)), 0.25g of glyceryl monostearate (Riken Vitamin: Glyceryl Monostearate P-100), 0.1g of polysorbate (Sanyo Chemical Industries: Polysorbate 80), 1g of succinic acid (Fuso Chemical Industries), 0.25g of titanium dioxide (Toho Titanium: NA-61), and 5.65g of purified water. 31.0g of granular material was then placed in a tumbling fluidized bed granulator (Powrec: FD-MP-micro) and the coating was carried out. The obtained granules were sized using a sieve with a screen diameter of 850 μm. 3.2 g of the sized coated granules were mixed with 17.48 g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1 g of crospovidone (BASF: Kollidon CL-F), and 0.22 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), an orally disintegrating tablet of the comparative example with a diameter of 8 mm and a mass of 0.22 g was obtained.

[0059] Table 2 shows the formulations for Examples 5-9 and Comparative Example 3.

[0060] [Table 2] [Examples]

[0061] 40.08 g of vonoprazan fumarate, 3.21 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P), and 0.75 g of talc (Matsumura Sangyo Co., Ltd.: Crown Talc Pharmacopoeia PP) were mixed and melt-granulated using a rolling fluid bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. 2.936g of whole granules was mixed with 17.744g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1g of croscarmellose sodium (Asahi Kasei Co., Ltd.: Kikkolate ND-200), and 0.22g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0062] 40.08 g of vonoprazan fumarate, 3.21 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P), 0.75 g of talc (Matsumura Sangyo Co., Ltd.: Crown Talc Pharmacopoeia PP), and 8.91 g of titanium dioxide (Toho Titanium Co., Ltd.: NA-61) were mixed and melt-granulated using a rolling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. 3.827g of whole granules was mixed with 16.853g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1g of croscarmellose sodium (Asahi Kasei Co., Ltd.: Kikkolate ND-200), and 0.22g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0063] 40.08 g of vonoprazan fumarate, 3.21 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P), 0.75 g of talc (Matsumura Sangyo Co., Ltd.: Crown Talc Pharmacopoeia PP), and 26.72 g of titanium dioxide (Toho Titanium Co., Ltd.: NA-61) were mixed and melt-granulated using a rolling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. 5.608g of whole granules was mixed with 15.072g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1g of croscarmellose sodium (Asahi Kasei Co., Ltd.: Kikkolate ND-200), and 0.22g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0064] 40.08 g of vonoprazan fumarate, 3.21 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P), 0.75 g of talc (Matsumura Sangyo Co., Ltd.: Crown Talc Pharmacopoeia PP), and 0.27 g of yellow iron(III) oxide (Kishi Kasei Co., Ltd.: Yellow Iron(III) oxide) were mixed and melt-granulated using a rolling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. 2.963g of whole granules was mixed with 17.717g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1g of croscarmellose sodium (Asahi Kasei Co., Ltd.: Kikkolate ND-200), and 0.22g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained. [Examples]

[0065] 40.08 g of vonoprazan fumarate, 3.21 g of glyceryl monostearate (Riken Vitamin Co., Ltd.: Rikemar S-100P), 0.75 g of talc (Matsumura Sangyo Co., Ltd.: Crown Talc Pharmacopoeia PP), and 2.67 g of yellow iron(III) oxide (Kishi Kasei Co., Ltd.: Yellow Iron(III) oxide) were mixed and melt-granulated using a rolling fluidized bed granulator (Powrec Co., Ltd.: FD-MP-micro). The resulting granules were sized using a sieve with a screen diameter of 500 μm. 3.203g of whole granules was mixed with 17.477g of D-mannitol, low-substituted hydroxypropylcellulose, and polyvinyl alcohol (fully saponified) granules (Shin-Etsu Chemical Co., Ltd.: SmartEX Q-100), 1.1g of croscarmellose sodium (Asahi Kasei Co., Ltd.: Kikkolate ND-200), and 0.22g of magnesium stearate (Taihei Chemical Industry Co., Ltd.: magnesium stearate, plant-derived). By using the mixed granules obtained above and compressing them with a rotary tablet press (Kikusui Seisakusho: VEL5), orally disintegrating tablets of the present invention with a diameter of 8 mm and a mass of 0.22 g were obtained.

[0066] [Table 3]

[0067] 《Test Example 1: Syringe Upside Down Method》 For Examples 1-9, Comparative Examples 1-3, and Reference Example 1 (Takecab® OD Tablets 20 mg (Takeda Pharmaceutical Company Limited)), the inverted syringe method was used. A 10 mL plastic syringe was prepared, fitted with a 25 mm size filter (Merck Millex-LH) with a 0.45 μm opening at the tip. A vonoprazan fumarate-containing orally disintegrating tablet equivalent to 20 mg of vonoprazan was placed in this syringe, and 5 mL of water maintained at 37 ± 1°C was added. Simultaneously, a piston was attached, and injections were administered 10 times over 30 seconds at a rate of once every 3 seconds, in an inverted syringe. The amount of vonoprazan was then filtered and measured.

[0068] The amount of vonoprazan was measured as follows: One mL of the recovered filtrate was used as the test solution. Separately, approximately 5 mg of vonoprazan fumarate standard was accurately weighed out, 8 mL of methanol was added, and the solution was dissolved by sonication. Methanol was then added to make a total volume of exactly 10 mL. One mL of this solution was accurately weighed out, and water was added to make a total volume of exactly 20 mL, which was used as the standard solution. This standard solution and the test solution were analyzed by HPLC under the following conditions, and the elution amount and elution rate were determined using the cumulative areas As and At of vonoprazan, according to equations (1) and (2) below, using the inverted syringe method. Elution amount (mg) when the syringe is turned upside down = Ws×At / As / 40 (1) Elution rate (%) with syringe inverted position=elution amount / 20×100...(2) Ws: Amount of vonoprazan fumarate standard (mg) Test conditions for the HPLC method Detector: UV absorbance spectrophotometer (measurement wavelength: 245 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm octadecylsilylated silica gel for liquid chromatography. Column temperature: Constant temperature around 40°C Mobile phase A: To a solution of 3.12 g of sodium dihydrogen phosphate dissolved in 1000 mL of water, add a solution of 0.43 g of sodium hydroxide dissolved in 100 mL of water to adjust the pH to 5.0. Add 500 mL of methanol to 500 mL of this solution. Area measurement time: 10 minutes Flow rate: 1.0 mL per minute

[0069] The results of the syringe inverted method are shown in Table 4.

[0070] [Table 4] Results and Discussion

[0071] Examples 1-9, by incorporating a low-melting-point substance, showed that the amount of vonoprazan dissolved in 5 ml of water at 37°C was suppressed compared to Comparative Examples 1-3, and orally disintegrating tablets containing vonoprazan fumarate with excellent bitterness masking properties were obtained.

[0072] 《Test Example 2: Tablet Hardness Measurement》 The tablet hardness of Examples 1 to 14 was evaluated using a tablet hardness tester (manufactured by PHARMA TEST), applying the tablet hardness measurement method of the 18th revised Japanese Pharmacopoeia.

[0073] The test results are shown in Table 5.

[0074] [Table 5]

[0075] As a result, as shown in Table 5, all of the orally disintegrating tablets in Examples 1 to 14 had a tablet hardness of 50N or higher.

[0076] 《Test Example 3: Intraoral Disintegration Test》 The orally disintegrating time of the orally disintegrating tablets of Examples 1 to 14 was evaluated using a tricorp tester (manufactured by Okada Seiko).

[0077] The test results are shown in Table 6.

[0078] [Table 6]

[0079] As a result, as shown in Table 6, all of the orally disintegrating tablets in Examples 1 to 14 had an orally disintegrating time of 60 seconds or less.

[0080] 《Test Example 4: Photostability Test》 For Examples 5, 7, and 10-14, each sample was stored under 3000 Lux·hr irradiation conditions until the total irradiation dose reached 1.2 million Lux·hr, and then a photostability test was performed. Purity tests were then conducted on the stored samples. The tablets were crushed into a powder, and a precise amount equivalent to 10 mg of vonoprazan fumarate was measured. After adding a water / acetonitrile mixture (7:3) and sonicating, the solution was reduced to exactly 10 mL, centrifuged, and filtered through a membrane filter with a pore size of 0.45 μm or less. The filtrate was used as the sample solution, and its purity was calculated by liquid chromatography. The ultraviolet absorbance of vonoprazan was measured at 252 nm. The results of the purity test are shown in Table 7. In Example 10, the total amount of related substances increased to 0.57% at a total irradiation dose of 1.2 million Lux·hr. In Examples 11-14, which contained titanium dioxide or yellow iron(III) oxide, the increase in the total amount of related substances was suppressed as the amount of titanium dioxide or yellow iron(III) oxide increased. In Example 5, where the granules were coated with a coating agent, the increase in the total amount of related substances was suppressed compared to Example 10. Furthermore, in Example 7, where titanium dioxide was incorporated into the coating layer, the increase in the total amount of related substances was suppressed compared to Example 5.

[0081] [Table 7]

Claims

1. An orally disintegrating tablet containing granules containing vonoprazan fumarate and a low-melting-point substance with a freezing point of 60°C or lower, along with a pharmaceutical excipient.

2. The orally disintegrating tablet according to claim 1, wherein the granules contain fumaric acid or a salt thereof.

3. The orally disintegrating tablets according to claims 1 and 2, wherein the granules are coated with one or more coating agents selected from hydrophilic additives and water-insoluble polymers.

4. An orally disintegrating tablet according to claim 1, wherein the granules contain one or more coloring agents selected from the group consisting of ferric oxide, yellow ferric oxide, black iron oxide, titanium dioxide, talc, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, and food blue No.

3.

5. The orally disintegrating tablet according to claim 1, wherein the low melting point substance with a freezing point of 60°C or less is one or more selected from the group consisting of macrogol, monoglyceryl stearate, cetanol, and polyoxyl stearate 40.

6. The orally disintegrating tablet according to claim 3, wherein the water-insoluble polymer is one or more selected from the group consisting of ethylcellulose, methacrylate copolymer LD, aminoalkyl methacrylate copolymer E, ammoniaalkyl methacrylate copolymer, hypromellose acetate succinate, and hypromellose phthalate.

7. The orally disintegrating tablet according to claim 3, wherein the hydrophilic additive is one or more selected from the group consisting of D-mannitol, lactose monohydrate, isomalt, hydroxypropylcellulose, hypromellose, methylcellulose, povidone, and polyvinyl alcohol (partially hydrolyzed).

8. An orally disintegrating tablet according to claim 1, comprising one or more selected from the group consisting of excipients, disintegrants, sweeteners, fluidizers, and lubricants.

9. The orally disintegrating tablet according to claim 8, wherein the excipient is one or more selected from the group consisting of D-mannitol, lactose monohydrate, isomalt, erythritol, trehalose, crystalline cellulose, and corn starch.

10. The orally disintegrating tablet according to claim 8, wherein the disintegrant is one or more selected from the group consisting of crospovidone, low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, croscarmellose calcium, and croscarmellose starch sodium.

11. The orally disintegrating tablet according to claim 8, wherein the sweetener is one or more selected from the group consisting of sucralose, aspartame, acesulfame potassium, and thaumatin.

12. The orally disintegrating tablet according to claim 8, wherein the fluidizing agent is one or more selected from the group consisting of light anhydrous silicic acid, hydrated silicon dioxide, and talc.

13. The orally disintegrating tablet according to claim 8, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, and hydrogenated oil.

14. An orally disintegrating tablet according to claim 1, comprising 10% by weight or more of granules per tablet.

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