Orally disintegrating tablet comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine, and method for preparing same

Abstract

The present invention relates to an orally disintegrating tablet comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine, the tablet having excellent dissolution characteristics and taste-masking performance.

Description

Oral disintegrating tablet containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine and method for manufacturing the same

[0001] The present invention relates to an orally disintegrating tablet comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine and a method for manufacturing the same.

[0002]

[0003] Gastroesophageal reflux disease (GERD) is defined as a condition in which stomach contents reflux into the esophagus or mouth, causing uncomfortable symptoms or complications. GERD is known to be a complex clinical condition involving various factors, including esophagogastric junction (EGJ) dysfunction, hypotension of the lower esophageal sphincter (LES), hiatal hernia, reflux in a supine position, and reduced esophageal acid clearance capacity. Typical symptoms include heartburn and non-cardiac chest pain; acid reflux can induce bronchospasm, and in severe cases, warning signs such as dysphagia (difficulty swallowing) and odynophagia (pain during swallowing) may appear. These symptoms may suggest the presence of esophageal strictures, ulcers, or malignant tumors.

[0004]

[0005] Treatment methods for gastroesophageal reflux disease include antacids, H₂ receptor antagonists, proton pump inhibitors (PPIs), and potassium-competitive acid blockers (P-CABs), depending on the severity of the disease. Among these, potassium-competitive acid blockers are known to have the advantage of rapidly raising gastric pH and having a long duration of action by competitively binding to gastric acid-secreting enzymes to rapidly and continuously inhibit gastric acid secretion.

[0006]

[0007] 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine is a pharmaceutical active ingredient described in Korean Patent Registration No. 10-1613245, and is a substance useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori by possessing excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori eradication activity, and GPCR inhibitory action.

[0008]

[0009] Meanwhile, in terms of drug administration, oral administration is the most preferred route due to convenience, the possibility of self-administration, and high patient compliance. However, for pediatric and elderly patients, particularly those with central nervous system disorders accompanied by dysphagia or gastroesophageal reflux disease, taking standard tablets or capsules can be difficult and may lead to a risk of choking. Consequently, there is an increasing demand for patient-friendly formulations to improve medication adherence in these patient groups.

[0010]

[0011] Recently, oral disintegrating tablets, oral disintegrating films, and mini tablets that rapidly disintegrate in the oral cavity through saliva have been proposed as patient-friendly formulations. Oral disintegrating tablets have the advantage of being able to be taken without water and having a low swallowing burden, but it has been pointed out that the bitter taste or unpleasant taste of the active ingredient may remain in the mouth for a long time, thereby hindering patient compliance.

[0012]

[0013] In particular, the above-mentioned 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine is known to be an effective drug for treating gastroesophageal reflux disease and gastritis; however, when applied in an orally disintegrating tablet formulation, the characteristic bitter taste is not sufficiently masked, leading to the problem of the substance remaining in the oral cavity. Therefore, research is needed on a formulation that contains the above-mentioned active ingredient, maintains appropriate disintegration and dissolution characteristics as an orally disintegrating tablet, and can effectively mask the bitter taste.

[0014]

[0015] Accordingly, research was conducted on the development of an oral disintegrating tablet containing 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine as an active ingredient, having dissolution characteristics suitable for an oral disintegrating tablet, and appropriately masking the bitter taste of the raw material. As a result, an oral disintegrating tablet with a coating agent was developed, thereby completing the present invention.

[0016]

[0017] The present invention is to provide an orally disintegrating tablet comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine or a pharmaceutically acceptable salt thereof, which exhibits excellent dissolution characteristics and taste masking properties, thereby having pharmaceutical properties suitable for oral administration, and a method for manufacturing the same.

[0018]

[0019] To solve the above problem, the present invention provides an orally disintegrating tablet comprising: a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; a granule comprising a pharmaceutically acceptable additive; a coating layer formed on the surface of the granule comprising a polymer-containing coating base; and a post-mixing agent.

[0020] [Chemical Formula 1]

[0021] .

[0022]

[0023] In addition, the present invention provides an orally disintegrating tablet comprising a coating pellet comprising: a core comprising an inert particle; a first coating layer formed on the core and comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and a second coating layer formed on the first coating layer and comprising a polymer-containing coating base.

[0024]

[0025] In addition, the present invention provides a method for manufacturing an orally disintegrating tablet, comprising the steps of: preparing a primary coating solution comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof (Step 1); forming a first coating layer by coating the primary coating solution onto a core comprising inert particles using a fluid bed granulator (Step 2); and forming a second coating layer by coating a coating composition comprising a polymer-containing coating agent onto the first coating layer to produce a coating pellet (Step 3).

[0026]

[0027] Meanwhile, in this specification, "particle size (D XThe statement ") = Y (where X and Y are positive numbers)" means that when the particle size distribution obtained by measuring particle diameters is represented by a cumulative curve, the particle diameter at the point where the accumulation of particles in order of smallest diameter reaches X% (where % is calculated based on number, volume, or weight) is Y. Therefore, particle diameter (D 10 ) refers to the diameter of the particle at the 10% point on the cumulative curve of the particle size distribution, and the particle diameter (D 50 ) refers to the diameter of the particle at the 50% point on the cumulative curve of the particle size distribution, and the particle size (D 90 ) represents the particle diameter at the point where it reaches 90% on the cumulative curve of the particle size distribution. In addition, the above particle diameter (D X The percentage of the total accumulated particles may vary depending on whether it is based on number, volume, or weight, and methods for measuring particle size distribution and types of % related thereto are known in the art.

[0028]

[0029] At this time, particle size (D X It is preferable that the measurement be performed by the laser diffraction method, which records the particle size as the diameter of a volume-equivalent sphere. In other words, when measuring the particle size distribution by the laser diffraction method, the particle size (D X The value of X in ) represents the percentage calculated by volume averaging. Therefore, laser diffraction is sensitive to the volume of the particles and provides a volume-averaged particle size, which corresponds to the weight-averaged particle size when the density is constant.

[0030]

[0031] The measurement of the volume-average particle size distribution by such laser diffraction method can be performed using a commercially available device known to be based on the laser diffraction and scattering method based on Mie theory. For example, the Mastersizer laser diffraction device from Malvern Instruments can be used. The device utilizes the fact that scattering occurs when a helium-neon laser beam and a blue light-emitting diode are irradiated onto particles, causing a light scattering pattern to appear on a detector, and calculates the distribution of volume occupancy by particle diameter by interpreting this light scattering pattern according to Mie theory. It has the advantage of being capable of both dry and wet measurements.

[0032]

[0033] The chemical name of the compound represented by the above chemical formula 1 is 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine, which is a pharmaceutical active ingredient having a molecular weight of 410.41 and is a substance described in Korean Patent Registration No. 10-1613245.

[0034]

[0035] The compound represented by Chemical Formula 1 above is an active ingredient that exhibits pharmacological effects in the oral administration formulation above, and is a substance useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori by having excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.), Helicobacter pylori eradication activity, and GPCR inhibitory action.

[0036]

[0037] In addition, in addition to the compound represented by Formula 1, a pharmaceutically acceptable salt thereof may be used as the active ingredient exhibiting the pharmacological effect of the oral formulation of the present invention. As such a salt, any salt commonly used in the art, such as an acid addition salt formed by a pharmaceutically acceptable free acid, may be used without limitation. The term "pharmaceutically acceptable salt" in the present invention refers to any organic or inorganic addition salt of said compound at a concentration having a relatively non-toxic and harmless active effect on the patient, wherein the side effects caused by said salt do not impair the beneficial efficacy of the compound represented by Formula 1.

[0038]

[0039] A pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 above can be obtained by conventional methods using an inorganic acid or an organic acid. For example, a pharmaceutically acceptable salt can be obtained by dissolving the compound represented by Chemical Formula 1 in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an organic acid or an inorganic acid, filtering the precipitated crystals, and drying them. Alternatively, it can be prepared by drying the residue by applying a solvent or excess acid under reduced pressure in a reaction mixture to which an acid has been added, or by filtering the precipitated salt after adding another organic solvent. In this case, preferred salts may be salts derived from hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvate, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid. More preferably, the pharmaceutically acceptable salt of the compound represented by Formula 1 may be a hydrochloride salt or a fumarate salt.

[0040]

[0041] The compound represented by Chemical Formula 1 above, or its pharmaceutically acceptable salt, is a potassium-competitive acid secretion inhibitor (P-CAB) that exhibits excellent efficacy in treating conditions such as gastroesophageal reflux disease; however, due to the drug's inherent strong bitter taste, there are some issues in formulating it into oral disintegrating tablets for oral administration or for use without water. Furthermore, adding only simple sweeteners makes it difficult to fundamentally mask the bitter taste felt during the oral retention time; moreover, excessive attempts at taste masking may actually delay the disintegration rate of the tablet or reduce the dissolution rate within the gastrointestinal tract, resulting in a delayed onset of drug efficacy. Additionally, due to the characteristic of oral disintegrating tablets needing to dissolve rapidly in the mouth, there was a technical challenge of simultaneously ensuring appropriate pharmaceutical properties, such as sufficient tensile strength and crush resistance required during storage and distribution, while also achieving a smooth swallowing sensation without any foreign body sensation.

[0042]

[0043] The present invention was completed by confirming that an orally disintegrating tablet, in which a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is appropriately coated by a polymer-containing coating base, blocks the expression of a bitter taste of the drug in the oral cavity, exhibits excellent dissolution characteristics in the gastrointestinal environment, and possesses excellent pharmaceutical properties.

[0044]

[0045] First, the present invention provides an orally disintegrating tablet comprising: a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; a granule comprising a pharmaceutically acceptable additive; a coating layer formed on the surface of the granule comprising a polymer-containing coating base; and a post-mixing agent:

[0046] [Chemical Formula 1]

[0047] .

[0048]

[0049] In this specification, “granule” refers to an aggregate formed into particles having a specific size and shape.

[0050]

[0051] The granules included in the orally disintegrating tablet according to the present invention are a type of mixture comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. In addition, the coating agent described below is a target material to which the coating agent is applied.

[0052]

[0053] The above-described pharmaceutically acceptable additives are not particularly limited as long as they do not impede the pharmacological effects of the compound represented by Formula 1 described above and its pharmaceutically acceptable salt. For example, the above-described pharmaceutically acceptable additives may include one or more selected from the group consisting of excipients, lubricants, sweeteners, and binders.

[0054]

[0055] Among the above additives, excipients are pharmaceutically acceptable ingredients used to form a product shape that facilitates the administration of the active ingredient exhibiting the pharmacological effect of the orally disintegrating tablet. Commonly used excipients include microcrystalline cellulose, lactose monohydrate, sucrose, D-mannitol, starch, corn starch, hard anhydrous silica, anhydrous calcium hydrogen phosphate, cyclodextrin, and a mixture of mannitol and starch (granulated mannitol powder), and the orally disintegrating tablet may contain commonly used excipients without limitation. Preferably, it may be one or more selected from the group consisting of mannitol, microcrystalline cellulose, lactose monohydrate, and a mixture of mannitol and starch (granulated mannitol powder), and more preferably, it may be mannitol.

[0056]

[0057] Among the above additives, a lubricant is added to increase the fillability of the formulation and facilitate compression. One or more of talc, stearic acid, magnesium stearate, colloidal silicon dioxide, calcium stearate, sodium benzoate, sodium stearyl fumarate, glyceryl monolate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, zinc stearate, and paraffins may be used as the lubricant, but are not limited thereto. Preferably, talc or magnesium stearate may be used as the lubricant for ease of the manufacturing process.

[0058]

[0059] Among the above additives, the sweetener may include one or more selected from the group consisting of aspartame, sucralose, sucrose, dextrose, stevioic acid, citric acid, fructose, glucose, liquid glucose, and maltose. Preferably, aspartame may be used as the sweetener.

[0060]

[0061] Among the above additives, the binder enables the form of the formulation to be maintained. Hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinylpyrrolidone, copovidone, povidone, starch, colloidal silicon dioxide, lactose, polyethylene glycol, and mixtures thereof may be used as the binder, but are not limited thereto. Additionally, the binder may further include a small amount of plasticizer, lubricant, etc. as auxiliary components. Preferably, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof may be used.

[0062]

[0063] Meanwhile, the method of manufacturing the granules is not particularly limited, but can be manufactured using a commonly known wet granulation method or a dry granulation method. For example, it can be manufactured by applying a wet granulation method in which a compound represented by Chemical Formula 1 described above, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive are mixed in a solvent, wherein the solvent may be water.

[0064]

[0065] In addition, the orally disintegrating tablet of the present invention may contain 30 to 95 weight% of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof based on the total weight of the granules, preferably 30 to 90 weight%, 30 to 80 weight%, 30 to 70 weight%, 30 to 60 weight%, more preferably 30 to 55 weight%, or 35 to 45 weight%. When the active ingredient is included in the above range, the characteristic bitter taste can be effectively masked without impairing the pharmacological effect of the active ingredient.

[0066]

[0067] In addition, the orally disintegrating tablet of the present invention comprises a coating layer formed on the surface of the granule and containing a polymer-containing coating base. The coating layer functions as a taste masking layer that improves compliance by physically shielding the characteristic bitter taste of the active ingredient, the compound represented by Formula 1 or its pharmaceutically acceptable salt. Furthermore, it performs the role of protecting the active ingredient from external moisture to ensure the stability of the formulation and controlling rapid disintegration within the oral cavity.

[0068]

[0069] In addition, the polymer-containing coating base is a key component for forming a continuous film of the coating layer. The polymer may be a water-insoluble polymer. The water-insoluble polymer includes a pharmaceutical polymer that acts as a physical barrier by rapidly dissolving in an acidic environment (approx. pH 1.2) while remaining insoluble in water or swelling under neutral oral conditions, thereby shielding the bitter taste of the drug even if the orally disintegrating tablet disintegrates within seconds in the mouth. Additionally, the coating base may be formulated with additives such as surfactants, emulsifiers, and lubricants along with the polymer to increase the flexibility and process efficiency of the coating, as needed.

[0070]

[0071] The above polymer may specifically be a (meth)acrylate-based polymer or a cellulose-based polymer. For example, the above polymer may include one or more of a (meth)acrylate-based polymer and alkylcellulose.

[0072] The above (meth)acrylate-based polymer may be a homopolymer or a copolymer. The above (meth)acrylate-based polymer may be one or more of a homopolymer and copolymer of one or more monomers selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, aminoalkyl (meth)acrylate, (meth)acrylic acid ester, and ammonio (meth)acrylate. In this case, the alkyl group in each monomer is not particularly limited, but may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, pentyl, 2-ethylhexyl, 2-ethylbutyl, n-octyl, isooctyl, isononyl, lauryl, tetradecyl, etc.

[0073] Specifically, the aminoalkyl (meth)acrylate copolymer may be a copolymer of aminoalkyl (meth)acrylate and one or more alkyl (meth)acrylates, and more specifically, may include a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO). In addition, the (meth)acrylic acid and alkyl (meth)acrylate copolymer may include a methacrylic acid and ethyl acrylate copolymer (e.g., Eudragit L 100, Eudragit L100-55), and the ammonio(meth)acrylate copolymer may include an ammoniomethacrylate copolymer (e.g., Eudragit RS, Eudragit RL).

[0074] In addition, the above-mentioned cellulose-based polymer refers to a cellulose derivative in which the hydroxyl groups of cellulose are substituted with alkyl groups or hydroxyalkyl groups. Preferably, it may be alkylcellulose, and more preferably, it may be ethylcellulose.

[0075] Preferably, the polymer may comprise one or more selected from the group consisting of a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; a copolymer of methacrylic acid and ethyl acrylate; an ammoniomethacrylate copolymer; and ethyl cellulose.

[0076]

[0077] In addition, the coating layer may further include one or more selected from the group consisting of surfactants, emulsifiers, and lubricants.

[0078]

[0079] The above surfactant improves the dispersibility of the polymer and controls the wettability of the coating layer, and the above surfactant may use sodium lauryl sulfate, polyethylene glycol, poloxamer, polysorbate (polysorbate 20, 40, 60, 80) and mixtures thereof, but is not limited thereto.

[0080]

[0081] The above emulsifier helps to uniformly mix the coating base components and provides flexibility to the film, and may include stearic acid, glyceryl monostearate, or sorbitan ester, etc.

[0082]

[0083] Refer to the description and specific types of the above-mentioned lubricant. Additionally, the lubricant included in the coating layer may be the same as or different from the lubricant included in the granules, and preferably, it is talc.

[0084]

[0085] In addition, in the orally disintegrating tablet of the present invention, the coating layer may be included in an amount of 50 to 90 parts by weight based on 100 parts by weight of the granules. If the content of the coating layer is less than the above range, the bitter taste of the active ingredient may not be sufficiently masked, and if it exceeds the above range, the overall size of the tablet may increase, thereby reducing convenience of administration or delaying the disintegration speed; therefore, optimal taste masking effect and disintegration characteristics can be achieved simultaneously within the above range. Preferably, the coating layer may be included in an amount of 55 parts by weight or more, 56 parts by weight or more, 57 parts by weight or more, 58 parts by weight or more, 59 parts by weight or more, or 60 parts by weight or more, and 90 parts by weight or less, 87 parts by weight or less, 85 parts by weight or less, 83 parts by weight or less, or 80 parts by weight or less, based on 100 parts by weight of the granules.

[0086]

[0087] In addition, in the oral disintegrating tablet of the present invention, the above-mentioned mixture may include one or more selected from the group consisting of excipients, disintegrants, sweeteners, flavoring agents, coloring agents, and lubricants.

[0088]

[0089] The above-mentioned mixture is added to the outer liquid of the coated granules after the coating treatment is completed, and acts as a buffer to prevent damage to the coating layer during tablet compression, while also providing appropriate hardness to the tablet and helping the tablet to decompose quickly within seconds by saliva in the oral cavity.

[0090]

[0091] Refer to the description above for the explanation and specific types of excipients included in the above-mentioned mixture. Preferably, a mixture of mannitol and starch (granulated mannitol powder) designed to enable direct tableting may be used.

[0092]

[0093] In addition, the above disintegrant may include crospovidone, sodium croscarmellose, or low-substituted hydroxypropylcellulose as an ingredient that accelerates moisture penetration into the tablet due to its high affinity for water.

[0094]

[0095] In addition, the above-mentioned mixture may include a multiple blend of aspartame, neohesperidin, sucralose, etc. as sweeteners to completely eliminate the residual bitter taste of the active ingredient. Additionally, it may include an appropriate amount of flavoring agents such as peppermint or lemon to reduce aversion when ingested, and coloring agents to enhance visual distinctiveness. The above-mentioned lubricant may include magnesium stearate or colloidal silicon dioxide, etc., to prevent adhesion with the punch during the tablet compression process.

[0096]

[0097] In addition, the orally disintegrating tablet of the present invention may contain a post-mixture in an amount of 50 to 90 weight% based on the total weight of the orally disintegrating tablet. When the content of the post-mixture is within the above range, the mechanical strength (hardness) of the tablet can be maintained while containing a large amount of coating particles, and at the same time, the target disintegration time in the oral cavity can be stably achieved. Preferably, the post-mixture may contain 55 to 85 weight% based on the total weight of the orally disintegrating tablet.

[0098]

[0099] Meanwhile, the present invention provides an orally disintegrating tablet comprising a coating pellet comprising: a core comprising an inert particle; a first coating layer formed on the core and comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and a second coating layer formed on the first coating layer and comprising a polymer-containing coating base.

[0100]

[0101] In the present invention, the inactive particles included in the core refer to pharmacologically inactive particles of any form. Specifically, the inactive particles may be a type of pharmaceutical additive that is a substance of a regular or irregular form that does not contain a substance having pharmacological activity. The inactive particles may be soluble, insoluble, or a combination thereof. In the present invention, the inactive particles may form the core alone or mixed with other additives, and may serve as a seed for coating the first coating layer and the second coating layer described below in the orally disintegrating tablet of the present invention.

[0102]

[0103] The shape of the above-mentioned inert particles is not particularly limited, but may be spherical. Additionally, specific examples of the above-mentioned inert particles may include one or more selected from the group consisting of sucrose, microcrystalline cellulose, mannitol, sorbitol, microcrystalline wax, silicon dioxide, lactose hydrate, and mixtures thereof.

[0104]

[0105] In addition, the average particle size (D) of the core above 50 The particle size of the core may be 50 to 400 μm. If the particle size of the core is less than 50 μm, aggregation between particles may occur during the coating process, making it difficult to form a uniform coating layer; if it exceeds 400 μm, it may cause a rough foreign body sensation when the finally manufactured orally disintegrating tablet disintegrates in the oral cavity, thereby reducing medication compliance. Therefore, by using a core within the above range, process efficiency and ease of administration can be secured simultaneously. Preferably, the average particle size (D) of the core 50 ) may be 60 µm or more, 70 µm or more, 80 µm or more, 90 µm or more, 100 µm or more, 110 µm or more, 120 µm or more, 130 µm or more, 140 µm or more, 150 µm or more, 160 µm or more, 170 µm or more, 180 µm or more, 190 µm or more, or 200 µm or more, and may be 395 µm or less, 390 µm or less, 385 µm or less, 380 µm or less, 375 µm or less, 370 µm or less, 365 µm or less, or 360 µm or less.

[0106]

[0107] In addition, the oral disintegrating tablet of the present invention comprises a first coating layer comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof on a core containing the inactive particles. That is, the oral disintegrating tablet of the present invention has a structure in which a first coating layer comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, which is a pharmaceutically active ingredient, surrounds the core and is laminated.

[0108]

[0109] In addition, in addition to the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the first coating layer may further include one or more selected from the group consisting of binders, surfactants, lubricants, and sweeteners.

[0110]

[0111] For the description and specific types of the above-mentioned binders, surfactants, lubricants, and sweeteners, refer to the above.

[0112] Preferably, the binder may be hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-viscosity hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and mixtures thereof, but is not limited thereto. In addition, the binder may further include plasticizers, lubricants, etc. as auxiliary components.

[0113] Preferably, considering the characteristics of the formulation, polysorbate (polysorbate 20, 40, 60, 80) and mixtures thereof may be used as the surfactant, but are not limited thereto.

[0114] Preferably, talc or magnesium stearate may be used as the lubricant in terms of ease of the manufacturing process.

[0115] Preferably, the sweetener may include one or more selected from the group consisting of aspartame, sucralose, sucrose, dextrose, stevioic acid, citric acid, fructose, glucose, liquid glucose, and maltose.

[0116]

[0117] In addition, the first coating layer comprises a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof with an average particle size (D 50 It may include finely divided particles of 20 μm or less.

[0118] Preferably, the average particle size (D) of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof included in the first coating layer. 50 The average particle size may be 20 μm or less, 17 μm or less, 15 μm or less, 13 μm or less, 12 μm or less, 11 μm or less, 10 μm or less, 9 μm or less, 8 μm or less, 7 μm or less, 6 μm or less, 5 μm or less, 4 μm or less, 3 μm or less, or 2 μm or less. Meanwhile, the lower limit of the average particle size is not particularly limited, but may be 0.1 μm or more, 0.2 μm or more, or 0.3 μm or more.

[0119] With conventional mixing methods, it is difficult to control the particle size distribution of the API, which can lead to a decrease in coating yield. Accordingly, in the present invention, the active ingredient is finely pulverized through a grinding process as needed to maximize dispersion stability within the suspension, and the active ingredient is uniformly and firmly attached to the surface of inactive particles, thereby enabling the achievement of high yield and content.

[0120] Meanwhile, as described below, the grinding process may involve dispersing granules containing a compound represented by Chemical Formula 1, which is an active ingredient, or a pharmaceutically acceptable salt thereof, in a dispersion solution, and then pulverizing them through a wet grinding process, specifically a bead-milling process. Additionally, a primary coating solution may be prepared by performing a dry grinding process, such as jet milling, on the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0121]

[0122] Meanwhile, the average particle size (D) of the core and the first coating layer is 50The average particle size (D) may be 100 to 450 μm. If the average particle size is excessively small (less than 100 μm) after the first coating layer is coated on the core, particle aggregation is accelerated during the subsequent formation of the second coating layer, which may cause a sharp decrease in process yield; if it exceeds 450 μm, the size of the final coated pellet becomes enlarged, which not only causes a foreign body sensation in the oral cavity but also increases the risk of pellet breakage during tablet compression, potentially degrading drug release control and taste masking performance. Therefore, maintaining the above particle size range allows for the simultaneous achievement of process stability and pharmaceutical completeness. Preferably, the average particle size (D) of the core and the first coating layer 50 ) may be 110 µm or more, 120 µm or more, 130 µm or more, 140 µm or more, 150 µm or more, 160 µm or more, 170 µm or more, 180 µm or more, 190 µm or more, or 200 µm or more, and 420 µm or less, 400 µm or less, 390 µm or less, 380 µm or less, 370 µm or less, 360 µm or less, 350 µm or less, 340 µm or less, 330 µm or less, 320 µm or less, 310 µm or less, or 300 µm or less.

[0123]

[0124] In addition, the present invention comprises a second coating layer formed on the first coating layer and comprising a polymer-containing coating base. The second coating layer serves as an outer layer for improving medication compliance by blocking a strong bitter taste derived from a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof contained in the first coating layer, and inhibits the immediate dissolution of the active ingredient in the oral cavity by coating the first coating layer.

[0125]

[0126] At this time, refer to the description and specific types of polymer-containing coating agents.

[0127] Specifically, the polymer may be a water-insoluble polymer. Additionally, specifically, the polymer may be a (meth)acrylate-based polymer. The (meth)acrylate-based polymer may be one or more of homopolymers and copolymers of one or more monomers selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, aminoalkyl (meth)acrylate, (meth)acrylic acid ester, and ammonio (meth)acrylate.

[0128] More specifically, it may be one or more selected from the group consisting of aminoalkyl (meth)acrylate copolymers, (meth)acrylic acid and alkyl (meth)acrylate copolymers and ammonio(meth)acrylate copolymers.

[0129] Preferably, the aminoalkyl (meth)acrylate copolymer may be a copolymer of an aminoalkyl (meth)acrylate and one or more alkyl (meth)acrylates, and specifically includes a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (e.g., Eudragit E PO). In addition, the (meth)acrylic acid and alkyl (meth)acrylate copolymer includes a methacrylic acid and ethyl acrylate copolymer (e.g., Eudragit L 100, Eudragit L100-55), and the ammonio(meth)acrylate copolymer includes an ammoniomethacrylate copolymer (e.g., Eudragit RS, Eudragit RL), etc. Furthermore, the polymer comprises a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; a methacrylic acid and ethyl acrylate copolymer; It may include one or more selected from the group consisting of and ammoniomethacrylate copolymers.

[0130] More preferably, in terms of the structure of the orally disintegrating tablet and the ease of the coating process, it may be a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (Eudragit E PO). Additionally, the polymer-containing coating base may be a single component of the copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, or it may be a mixture in which additives such as surfactants, emulsifiers, and lubricants are mixed together.

[0131]

[0132] In addition, the second coating layer may further include one or more additives selected from the group consisting of surfactants, emulsifiers, and lubricants to increase the efficiency and stability of the coating.

[0133] For the description and specific types of the above surfactants, emulsifiers, and lubricants, refer to the above.

[0134] Preferably, sodium lauryl sulfate may be used as the surfactant, taking into account the characteristics of the polymer-containing coating base, but is not limited thereto.

[0135] Preferably, the emulsifier may include stearic acid, etc.

[0136] Meanwhile, the lubricant included in the second coating layer may be the same as or different from the lubricant included in the first coating layer, and preferably, talc or magnesium stearate may be used in terms of ease of the manufacturing process.

[0137]

[0138] The orally disintegrating tablet of the present invention comprises a coating pellet comprising the aforementioned core, a first coating layer, and a second coating layer. As such, the coating pellet included in the orally disintegrating tablet of the present invention has a structure in which a first coating layer containing an active ingredient and a second coating layer for taste masking are independently separated and laminated, thereby representing a solid formulation capable of simultaneously optimizing drug release control and bitter taste masking effects.

[0139]

[0140] Additionally, the coating pellet may contain the second coating layer in an amount of 30 to 200 parts by weight, based on 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. If the second coating layer is contained in an amount less than 30 parts by weight, it is difficult to expect a sufficient taste-masking effect, and a bitter taste may persist; if it is contained in an amount exceeding 200 parts by weight, the particle size of the pellet becomes excessively large, which may cause a foreign body sensation in the oral cavity or excessively delay the drug dissolution rate. Therefore, maintaining the content of the second coating layer within the above range allows for balanced control of taste-masking performance and pharmaceutical characteristics. Preferably, based on 100 parts by weight of the compound represented by Formula 1 or the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, the second coating layer may be included in an amount of 33 parts by weight or more, 35 parts by weight or more, 37 parts by weight or more, 40 parts by weight or more, 43 parts by weight or more, 45 parts by weight or more, 47 parts by weight or more, or 50 parts by weight or more, and 190 parts by weight or less, 180 parts by weight or less, 170 parts by weight or less, 160 parts by weight or less, or 155 parts by weight or less.

[0141]

[0142] In addition, the average particle size (D) of the coating pellets is 50The particle size may be 120 to 500 μm. If the particle size of the coating pellet is less than 120 μm, the amount of coating solution required for taste masking increases excessively due to the high surface area of ​​the fine particles, and frequent particle aggregation may occur, potentially lowering process efficiency; if it exceeds 500 μm, a sandy sensation may be felt after the tablet disintegrates in the oral cavity, significantly reducing medication compliance. Preferably, the average particle size (D) of the coating pellet 50 ) may be 120 µm or more, 130 µm or more, 135 µm or more, 140 µm or more, 145 µm or more, 150 µm or more, 155 µm or more, 160 µm or more, 165 µm or more, 170 µm or more, 175 µm or more, or 180 µm or more, and may be 470 µm or less, 450 µm or less, 430 µm or less, 420 µm or less, 410 µm or less, or 400 µm or less.

[0143]

[0144] In addition, the oral disintegrating tablet of the present invention may further include a post-mixing agent comprising one or more selected from the group consisting of excipients, disintegrants, sweeteners, flavoring agents, coloring agents, and lubricants, in addition to the coating pellets described above.

[0145] For the description and specific types of the above excipients, sweeteners, flavorings, and lubricants, refer to the above.

[0146] Preferably, as the excipient, a mixture of mannitol and starch (granulated powder mannitol), microcrystalline cellulose, or a mixture thereof designed to be included in the subsequent mixture to enable direct tableting may be used.

[0147] Preferably, crospovidone can be used as the disintegrant in that it can further improve storage stability without causing a decrease in dissolution rate and content under conditions similar to the gastrointestinal environment of the living organism.

[0148] Preferably, the sweeteners included in the subsequent mixture may include one or more selected from aspartame, sucralose, sucrose, dextrose, fructose, glucose, liquid glucose, or maltose.

[0149] Meanwhile, the above-mentioned flavoring agent may use peppermint microns, orange microns, raspberry microns, cherry scent, etc.

[0150] In addition, the coloring agents included in the above-mentioned mixture include, but are not limited to, titanium oxide, yellow iron oxide, red iron oxide, black iron oxide, titanium dioxide, talc, and green coloring agents (pigment blend-green). Preferably, for aesthetic purposes, a green coloring agent may be used as the coloring agent.

[0151] In addition, the lubricant included in the above-mentioned mixture may be the same as or different from the lubricant included in the first coating layer and the second coating layer, and preferably, talc, magnesium stearate, colloidal silicon dioxide, or a mixture thereof is used in terms of ease of manufacturing process.

[0152]

[0153] In addition, the coating pellet may be included in an amount of 10 to 35 weight% based on the total weight of the orally disintegrating tablet. If the content of the coating pellet is less than 10 weight%, there are limitations in formulating a high dose of the active ingredient and the size of the tablet may become unnecessarily large; if it exceeds 35 weight%, problems such as a foreign body sensation in the oral cavity or a delayed disintegration time may occur. Therefore, by maintaining the pellet content within the above range, appropriate hardness of the tablet can be secured, the disintegration time can be achieved at a desired level, and taste masking performance can be maintained. Preferably, based on the total weight of the orally disintegrating tablet, the coated pellets may be included in an amount of 11% or more by weight, 12% or more by weight, 13% or more by weight, 14% or more by weight, 15% or more by weight, 16% or more by weight, 17% or more by weight, 18% or more by weight, 19% or more by weight, or 20% or more by weight, and 34% or less by weight, 33% or less by weight, 32% or less by weight, 31% or less by weight, or 30% or less by weight.

[0154]

[0155] Meanwhile, the present invention provides a method for manufacturing an orally disintegrating tablet, comprising the steps of: preparing a primary coating solution containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof (Step 1); forming a first coating layer by coating the primary coating solution onto a core containing inert particles using a fluid bed granulator (Step 2); and forming a second coating layer by coating a coating composition containing a polymer-containing coating agent onto the first coating layer to produce a coating pellet (Step 3).

[0156]

[0157] The primary coating solution of Step 1 above may be a mixture comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; one or more selected from the group consisting of a binder, a surfactant, and a lubricant; and a solvent. For a description of the binder, surfactant, sweetener, and lubricant, refer to the description above. The solvent is purified water, ethanol, or a mixture thereof. Specifically, the mixture prepared in Step 1 may be in the form of a dispersion or suspension in which the active ingredient is dispersed as fine particles in the solvent, or in the form of a solution in which the active ingredient is completely dissolved in the solvent.

[0158]

[0159] In addition, in the preparation of the primary coating solution of Step 1, the mixture is a suspension, and the method may include a step of preparing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof into finely divided particles through a wet grinding process using a bead mill. Specifically, the wet grinding process may utilize a bead mill process, and the specific conditions of the bead mill process may be applied under conventional conditions. The average particle size (D) of the finely divided particles of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof within the suspension through the grinding process 50 The size can be adjusted to 20 μm or less, 17 μm or less, 15 μm or less, 13 μm or less, more specifically to 10 μm or less, 7 μm or less, 5 μm or less, 4 μm or less, 3 μm or less, 2 μm or less, 1.5 μm or less, 1.3 μm or less, or 1 μm or less, and the lower limit thereof is not specifically limited, but may be 0.1 μm or more, 0.2 μm or more, or 0.3 μm or more. This micronization step is intended to reduce the size of the main component particles to slow down the sedimentation or floating velocity of the particles in the liquid phase, thereby maximizing the dispersion stability of the suspension so that the active ingredient is uniformly attached to the surface of the inactive particles with a high yield during the subsequent coating process.

[0160]

[0161] Additionally, Step 1 may include the step of grinding a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof into finely divided particles, and mixing the finely divided particles with one or more selected from the group consisting of a binder, a surfactant, and a lubricant; and a solvent to prepare a mixed solution. That is, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may first be prepared into fine powder having a desired particle size through grinding, and then prepared into a mixed solution. At this time, a dry grinding process may be applied for the grinding process, and specifically, a Jet mill process may be applied. The average particle size (D) of the finely divided particles of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof obtained through the dry grinding process 50 ) may be 20 µm or less, 17 µm or less, 15 µm or less, 13 µm or less, 10 µm or less, 9 µm or less, 8 µm or less, 7 µm or less, 6 µm or less, 5 µm or less, 4 µm or less, 3 µm or less, or 2 µm or less, and the lower limit thereof is not specifically limited, but may be 0.1 µm or more, 0.2 µm or more, or 0.3 µm or more.

[0162]

[0163] In the subsequent Step 2 of the present invention, a first coating layer is formed by spraying and drying the first coating liquid onto inert particles using a Fluid Bed Granulator (FBG). During the coating process, the air supply temperature, liquid volume, and spray pressure can be controlled so that each coating process can be properly performed. The operating conditions of the Fluid Bed Granulator and the process of forming the first coating layer can be specified in the embodiments described below.

[0164]

[0165] In addition, in step 3 of the present invention, a coating composition containing a polymer-containing coating agent is coated on the surface of a primary coating material having the first coating layer formed thereon to form a second coating layer and produce a coating pellet. For the description of the polymer-containing coating agent and the additive for forming the second coating layer used at this time, refer to the above description.

[0166] In addition, a second coating layer can be formed using a fluidized bed granulator in step 3 of the present invention. At this time, the coating method is not particularly limited, but a bottom spray method may be used. The operating conditions of the fluidized bed granulator and the process of forming the second coating layer can be specified in the embodiments described later.

[0167]

[0168] In addition, the method for manufacturing an orally disintegrating tablet of the present invention may further include the step of mixing a manufactured coating pellet with one or more post-mixing agents selected from the group consisting of excipients, disintegrants, sweeteners, flavoring agents, coloring agents, and lubricants (step 4); and the step of compressing the mixture of step 4 into a tablet (step 5).

[0169]

[0170] Meanwhile, during the tableting process in Step 5 above, it is important to control the pressure to prevent damage to the coating film of the pellet. By compressing within an appropriate pressure range, the hardness of the tablet is maintained at a desired level to prevent damage during transport, while simultaneously allowing it to disintegrate quickly in the oral cavity so that the patient can take it gently.

[0171]

[0172] However, the present invention is not limited to such manufacturing methods, and the manufacture of orally disintegrating tablets can be modified according to methods known in the relevant technical field.

[0173]

[0174] As described above, the orally disintegrating tablet according to the present invention has excellent dissolution characteristics and taste masking effects, and has excellent pharmaceutical properties, making it useful as an orally disintegrating tablet for oral administration. This is explained in more detail in the experimental examples described below.

[0175]

[0176] As described above, the orally disintegrating tablet of the present invention comprising 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine or a pharmaceutically acceptable salt thereof is useful for gastroesophageal reflux disease due to its excellent dissolution characteristics and taste masking properties.

[0177]

[0178] Hereinafter, preferred embodiments are presented to aid in understanding the present invention; however, the following embodiments are merely illustrative of the invention and the scope of the invention is not limited to the following embodiments.

[0179]

[0180] Preparation Example 1-1

[0181] The hydrochloride salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine, which is the compound represented by the above chemical formula 1 (hereinafter abbreviated as “Fexuprazan HCl”), was prepared by the method described in the example of Korean Patent Registration No. 10-2126576.

[0182]

[0183] Preparation Example 1-2

[0184] A compound represented by the above chemical formula 1, 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine (hereinafter abbreviated as “Fexuprazan”), was prepared by the method described in the preparation example of Korean Patent Registration No. 10-2417830.

[0185]

[0186] Comparative Example 1-1

[0187] A mixture was prepared by mixing the Fexuprazan HCl of Preparation Example 1 above with each component listed in Table 1 below in the amounts listed in Table 1 below.

[0188] Specifically, the Fexuprazan HCl of Preparation Example 1, microcrystalline cellulose, lactose hydrate, and magnesium stearate were mixed. Subsequently, the mixture was compressed in a roller compactor to produce a plate-shaped compressed product, which was then crushed and granulated using an oscillator to produce dry granules. Sodium croscarmellose, yellow iron oxide, and magnesium stearate were added to the prepared granules and mixed, and the resulting mixture was compressed to produce a tablet (oral disintegrating tablet).

[0189]

[0190] Comparative Example 1-2

[0191] In Comparative Example 1-1 above, a tablet (oral disintegrating tablet) was prepared in the same manner as in Comparative Example 1-1, except that after preparing dry granules, aspartame and peppermint flavoring agents were further added to the prepared granules.

[0192]

[0193] Comparative Examples 1-3 to 1-5

[0194] A mixture was prepared by mixing the Fexuprazan HCl of the above preparation example, or Fexuprazan, with each component listed in Table 1 below in the amounts listed in Table 1 below. A tablet (oral disintegrating tablet) was prepared by direct compression of the resulting mixture.

[0195]

[0196] Classification Ingredient Amount (Parts by Weight) Comparative Example 1-1 Comparative Example 1-2 Comparative Example 1-3 Comparative Example 1-4 Comparative Example 1-5 API Fexuprazan HCl 100 100 100 100 - Fexuprazan ---- 100 Excipients Microcrystalline Cellulose 199.8 199.8 - 95.975 95.975 Excipients Lactose Hydrate 52.5 52.5 52.5 52.5 52.5 Excipients D-Mannitol -- 195.975 7575 Llullizer Magnesium Stearate 3.75 3.75 --- Coloring Agent Iron Oxide 0.2 0.2 0.2 --- Disintegrant Croscarmellose Sodium 15 15 15 15 15 Sweetener Aspartame - 35.75 7.5 32.5 32.5 Flavoring Agent Peppermint Flavoring - 0.25 0.075 0.25 0.25 Lubricant Magnesium Stearate 3.75 3.75 3.75 3.75 3.75

[0197] Comparative Examples 1-6 to 1-10

[0198] A mixture was prepared by dry mixing the Fexuprazan HCl of Preparation Example 1 and colloidal silicon dioxide, and a coating solution was prepared by adding the coating agent listed in Table 2 below to purified water and stirring thoroughly.

[0199] Subsequently, the above mixture was fed into a fluidized bed granulator (FBG), and the prepared coating solution was sprayed while flowing it (air supply temperature: 60 ℃, air supply volume: 40~70 m 3 / h, liquid volume: 10~30 g / min). Afterwards, the excipients, disintegrants, sweeteners, and flavoring agents listed in Table 2 below were added to the prepared particles and mixed, and the resulting mixture was compressed to produce tablets (oral disintegrating tablets).

[0200]

[0201] The substances and amounts used in Comparative Examples 1-6 to 1-10 above are summarized in Table 2 below.

[0202]

[0203] Amount of Ingredients Used for Formulation Purpose (Parts by Weight) Comparative Example 1-6 Comparative Example 1-7 Comparative Example 1-8 Comparative Example 1-9 Comparative Example 1-10 API Fexuprazan HCl 100 100 100 100 100 Fluidizing Agent Colloidal Silicon Dioxide 33 3 3 Coating Base Eudragit E PO Readymix (Eudragit E PO 55%) 30---50 Surelease (Ethylcellulose 25%) 120 120 80 - Solvent Purified Water 120 80 80 53.5 200 Excipient Mannitol and Starch Mixture (Pearlitol Flash) 76 27 67 827 81 280 Disintegrant Croscarmellose Sodium 5050---Sweetener Aspartame 2020303030 Sweetener Stevioside 1010---Sweetener Citric Acid---25-Flavoring Agent Raspberry Flavoring Agent 1510555 Lubricant Magnesium Stearate 10105551 Tablet Total Weight 10001000100010001000

[0204] Example 1-1

[0205] A binder (povidone) was dissolved in purified water to prepare a binder solution, and the Fexuprazan HCl of Preparation Example 1 was mixed with a lubricant (talc), an excipient (mannitol), and a sweetener (aspartame). Granules were prepared by spraying the binder solution while flowing it through a fluidized bed granulator (air supply temperature: 60℃, air supply volume: 70 m²). 3 / h, liquid volume: 30 g / min).

[0206] A coating base (Eudragit E PO), a surfactant, and an emulsifier were added to purified water, which is the solvent, and stirred with an overhead stirrer for 2 hours. Afterward, a lubricant was added and uniformly dispersed, and then filtered through a 0.5 mm sieve to prepare the coating solution.

[0207] While flowing the above-mentioned granules in a fluidized bed granulator, the above-mentioned coating solution was sprayed to produce granules with a coated surface (supply air temperature: 45 ℃, supply air flow rate: 80 m 3 / h, liquid volume: 17 g / min).

[0208] A tablet (oral disintegrating tablet) was prepared by mixing the above-mentioned coated granules with the mixture described in Table 3 below and compressing it.

[0209]

[0210] Examples 1-2

[0211] A tablet (oral disintegrating tablet) was prepared in the same manner as in Example 1-1, except that Fexuprazan of Preparation Example 2 was used instead of Fexuprazan HCl as the API when preparing the granules, and a coloring agent was further added as a subsequent mixing agent.

[0212]

[0213] The materials and amounts used in Examples 1-1 and 1-2 above are summarized in Table 3 below.

[0214]

[0215] Classification Purpose of Formulation Ingredient Amount (Parts by Weight) Example 1-1 Example 1-2 Granules API Fexuprazan HCl 100-Fexuprazan-9 1.75 Llubricant Talc 33 Excipient Mannitol 50 C 100 100 Sweetener Aspartame 2 2 2 Binder Povidone 17.5 17.5 Solvent Purified Water 140 140 Coating Layer Coating Base Eudragit E PO 90 90 Surfactant Sodium Lauryl Sulfate 99 Emulsifier Stearic Acid 13.5 13.5 Llubricant Talc 45 45 Solvent Purified Water 89 2.5 89 2.5 After Mixing Agent Excipient Mannitol and Starch Mixture (Pearlitol Flash) 5 10 50 8.15 Disintegrant Crospovidone 50 50 Sweetener Aspartame 25 25 Sweetener Neohesperidin 55 Flavoring Agent Cherry Flavoring Agent 510 Lubricant Magnesium Stearate 551 Tablets Total Weight (Parts by Weight) 1000 1000 Granules API Content (%) Based on Total Weight 4139 Coating Layer Content (Parts by Weight) Based on 100 Parts by Weight of Granules 65671 Subsequent Mixing Agent Content (%) Based on Total Weight 6061

[0216] Experimental Example 1

[0217] The tablets prepared in the above examples and comparative examples were evaluated for the following items.

[0218]

[0219] (1) Sensory evaluation

[0220] Sensory evaluations were conducted on healthy adult volunteers (e.g., n=10).

[0221] After rinsing their mouths thoroughly, each subject placed one tablet according to the above examples and comparative examples on their tongue without water. The bitter taste felt during the process of the tablet completely disintegrating in the saliva in the oral cavity and passing down the throat was quantified according to the evaluation criteria (Score) below. A sufficient rest period (e.g., 30 minutes or more) was allowed between evaluations of each tablet to ensure that no influence from the previous sample remained.

[0222] 0: Not bitter at all 1: Slightly bitter 2: Bitter 3: Strong but tolerable bitterness 4: Strong bitterness unbearable bitterness

[0223]

[0224] Sensory Evaluation Comparative Examples 1-13~4 Comparative Examples 1-24 Comparative Example 1-34 Comparative Example 1-44 Comparative Example 1-53 Comparative Example 1-62~3 Comparative Example 1-70~1 Comparative Example 1-80~1 Comparative Example 1-91~2 Comparative Example 1-102 Example 1-10~1 Example 1-20~1

[0225] (2) Elution evaluation

[0226] A comparative dissolution test was conducted between the reference drug (Comparative Example 1-1) and the test drugs (Comparative Examples 1-6 to 1-10 and Examples 1-1 and 1-2). The comparative dissolution test was performed in a pH 1.2 dissolution solution in accordance with the comparative dissolution test method in Annex 5-2 of the Standards for Pharmaceutical Equivalence Tests notified by the Ministry of Food and Drug Safety.

[0227]

[0228] Classification Average Dissolution Rate (%) 5 min 10 min 15 min 30 min Comparative Example 1-17 4.5 88.8 90.7 92.8 Comparative Example 1-6 59.5 74.1 78.2 84.6 Comparative Example 1-7 8.8 15.1 20.7 34.1 Comparative Example 1-8 4.7 9.8 13.8 22.0 Comparative Example 1-9 11.1 19.8 26.5 39.4 Comparative Example 1-10 16.3 22.1 26.6 37.2 Example 1-17 4.9 85.5 93.9 96.9 Example 1-28 5.6 90.9 91.2 91.9

[0229] (3) Tablet evaluation

[0230] The thickness, hardness, and disintegration time of the tablets of Comparative Examples 1-8 to 1-10 and Examples 1-1 and 1-2 after tablet compression were measured and are shown in Table 6 below. Hardness and disintegration time were measured by the following method.

[0231]

[0232] Hardness measurement

[0233] To evaluate physical strength, hardness was measured using a tablet hardness tester (Model MT50, SOTAX AG, Switzerland) according to the USP 1217 Tablet breaking force testing method.

[0234] Specifically, 10 tablets were randomly selected from each manufactured tablet. The selected tablets were placed in the radial direction on a hardness tester and pressed to measure the force at which the tablet broke. The mean value of the hardness values ​​of the 10 measured tablets was calculated and used as the final hardness. The unit of measurement was recorded in kiloponds (KP).

[0235]

[0236] Disintegration time measurement

[0237] United States Pharmacopoeia (USP) <701> The disintegration time was measured according to the disintegration test method.

[0238]

[0239] Thickness (mm) Hardness (KP) Disintegration Time (sec) Comparative Example 1-8 3.4 14.130 Comparative Example 1-9 3.4 12.628 Comparative Example 1-10 3.5 12.519 Example 1-1 3.7~3.8 5.6~7.017~30 Example 1-2 3.8 6.018

[0240] As can be seen from Tables 4 to 6 above, compared to the tablets of Comparative Examples 1-1 to 1-10, which were coated in a physical mixture or powder state with the main ingredient, the tablets of the Examples showed excellent taste masking, exhibited rapid release characteristics similar to the control drug, and had appropriate hardness and disintegration time.

[0241]

[0242] Preparation Example 2-1

[0243] Preparation of the first coating solution

[0244] A binder (Opadry 03K19229) was added to purified water and stirred with an overhead stirrer to prepare a binder solution. API (Fexuprazan HCl of Preparation Example 1) was added to the prepared binder solution and stirred to disperse it uniformly. The prepared API dispersion was fed into a bead mill (Netzsch, MiniCer, bead size 0.5 mm) and a grinding process was performed at a speed of 2500 rpm. During this process, the primary coating solution was prepared by continuously stirring with an overhead stirrer before, during, and after grinding. As a result of particle size analysis of the fine powder containing API in the prepared primary coating solution, D 10 Silver is 0.43 µm, D 50 Silver is 0.64 µm, D 90 It was 1.04 µm.

[0245]

[0246] Formation of the primary coating layer

[0247] Inert particles (spherical sugar (45 / 60 mesh)) were introduced into a fluid bed granulator (FBG) and flowed, and the first coating solution prepared above was sprayed to form a first coating layer on the core surface, thereby producing a first coating product.

[0248]

[0249] Coating Pellet Manufacturing

[0250] A coating base (Eudragit E PO), a surfactant (sodium lauryl sulfate), and an emulsifier (stearic acid) were added to purified water and stirred with an overhead stirrer for 2 hours. Afterward, a lubricant (talc) was added and uniformly dispersed, and then filtered through a 0.5 mm sieve to prepare a secondary coating solution (coating composition).

[0251] Next, the first coating material prepared above was introduced into a fluidized bed granulator and flowed, while spraying the second coating liquid prepared above to form a second coating layer on the surface of the first coating material, thereby producing a coating pellet.

[0252] In the above process, the operating conditions of the fluidized bed granulator are as described in Table 7 below.

[0253]

[0254] Preparation Example 2-2

[0255] Preparation of the first coating solution

[0256] A binder (hydroxypropyl methylcellulose (3 mPas)) and a lubricant (talc) were added to purified water and stirred with an overhead stirrer to prepare a binder solution. API (Fexuprazan HCl of Preparation Example 1) was added to the prepared binder solution and stirred to disperse it uniformly. The prepared API dispersion was fed into a bead mill (Netzsch, MiniCer, bead size 0.5 mm) and a grinding process was performed at a speed of 2500 rpm. During this process, the primary coating solution was prepared by continuously stirring with an overhead stirrer before, during, and after grinding. As a result of particle size analysis of the fine powder containing API in the prepared primary coating solution, D10 Silver is 0.42 µm, D 50 Silver is 0.62 µm, D 90 It was 0.99 μm.

[0257]

[0258] Formation of the primary coating layer

[0259] Inert particles (spherical sugar (100 / 140 mesh)) were introduced into a fluid bed granulator (FBG) and flowed, while spraying the first coating solution prepared above to form a first coating layer on the core surface, thereby producing a first coating product.

[0260]

[0261] Coating Pellet Manufacturing

[0262] A coating base (Eudragit E PO), a surfactant (sodium lauryl sulfate), and an emulsifier (stearic acid) were added to purified water and stirred with an overhead stirrer for 2 hours. Afterward, a lubricant (talc) was added and uniformly dispersed, and then filtered through a 0.5 mm sieve to prepare a secondary coating solution.

[0263] Next, the first coating material prepared above was introduced into a fluidized bed granulator and flowed, while spraying the second coating liquid prepared above to form a second coating layer on the surface of the first coating material, thereby producing a coating pellet.

[0264] In the above process, the fluid bed granulator operating conditions (FBG Parameter) are as described in Table 7 below.

[0265]

[0266] The materials and amounts used in the above Preparation Examples 2-1 and 2-2 are summarized in Table 7 below.

[0267]

[0268] Process Formulation Purpose Ingredient Usage (Parts by Weight) Preparation Example 2-1 Preparation Example 2-2 1st Coating Core Spherical Sugar (45 / 60 mesh) 250 - Core Spherical Sugar (100 / 140 mesh) - 125 API Fexuprazan HCl 100 100 Binder * Opadry 03K1922950 - Binder Hydroxypropyl Methylcellulose (3mPas) - 50 Lubricant Talc - 12.5 Solvent Purified Water 850 850 2nd Coating Coating Base Eudragit E PO90 90 Surfactant Sodium Lauryl Sulfate 99 Emulsifier Stearic Acid 13.5 13.5 Lubricant Talc 45 45 Solvent Purified Water 89 2.5 89 2.5 2nd Coating Layer Content (Parts by Weight) Based on 100 parts by weight of API 157.5 157.5 FBG Parameter 1st Coating 2nd Coating 1st Coating 2nd Coating Air Supply Temperature (°C) 50 45 → 34 50 45 → 35 Air Supply Volume (m 3 / h)60~7080~9040~10070~82Liquid volume (g / min)5.05.03.0~5.07.0Atomizing / Microclimate pressure (bar)0.8 / 0.050.8 / 0.050.8 / 0.050.8 / 0.05

[0269] *Opadry 03K19229: Mixture of hydroxypropyl methylcellulose (6 mPas), triacetin, and talc

[0270] Experimental Example 2

[0271] The coating pellets prepared in Manufacturing Examples 2-1 and 2-2 above were evaluated for the following items, and the results are shown in Table 8 below.

[0272]

[0273] (1) Average particle size (D 50 )

[0274] Particle size was measured before coating (core), after the first coating, and after the second coating using a laser diffraction analyzer (Mastersizer 3000, Malvern Instruments, UK) equipped with a dry powder separation unit (Aero S, Malvern, UK).

[0275]

[0276] (2) API content (Assay) evaluation

[0277] API content was measured using the liquid chromatography method (HPLC). Specifically, the test solution and standard solution were prepared separately, and the API content was calculated by comparing the peak areas of each solution on the HPLC.

[0278]

[0279] Preparation Example 2-1 Preparation Example 2-2 Average particle size (D 50 ) (㎛) Before coating 18 4 15 4 After 1st coating 2 2 5 20 3 After 2nd coating 2 5 12 3 7 API content (%) 100.0 (After 1st coating) 100.2 (After 2nd coating) 99.6 (After 2nd coating)

[0280] Examples 2-1 to 2-5

[0281] Oral disintegrating tablets were prepared by adding the following mixture described in Table 9 to the coating pellets of Preparation Example 2-1 or 2-2, mixing, and compressing. At this time, the oral disintegrating tablets were compressed to have a hardness of at least 6 KP.

[0282]

[0283] The materials and amounts used in Examples 2-1 to 2-5 above are summarized in Table 9 below. At this time, the amounts used are based on 100 parts by weight of API used in Preparation Examples 2-1 and 2-2 above.

[0284]

[0285] Amount of Process Ingredients Used (Parts by Weight) Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Preparation of Mixed Coated Pellet Example 2-1 200 300 400 -- Preparation Example 2-2 --- 445 445 Mannitol and Starch Mixture (Pearlitol Flash) 755 655 555 109 87.5 Aspartame 25 25 25 25 25 Green Coloring Agent 10 10 10 10 10 Peppermint Flavoring Agent 55 55 5 Magnesium Stearate 55 55 5 Total Weight (Parts by Weight) 1000 1000 1000 1000 147 7.5 Coated Pellet Content (%) Based on Total Weight 20 30 40 45 30

[0286] Experimental Example 3

[0287] The hardness and oral disintegration time of the orally disintegrating tablets prepared in Examples 2-1 to 2-5 above were measured, and the results are shown in Table 10 below. Hardness was measured in the same manner as in Experimental Example 1 above, and the oral disintegration time was evaluated by measuring the time it took for the tablet to disintegrate in the oral cavity.

[0288]

[0289] Example 2-1 Example 2-2 Example 2-3 Example 2-4 Example 2-5 Hardness (KP) approx. 6.0 10.5 Disintegration time (sec) 25 18 30 or more 30 or more 25

[0290] Example 3-1

[0291] Preparation of the first coating solution

[0292] A binder (low-viscosity hydroxypropyl cellulose) and a sweetener (aspartame) were added to purified water and stirred with an overhead stirrer to prepare a binder solution. API (Fexuprazan HCl of Preparation Example 1) was added to the prepared binder solution and stirred to disperse it uniformly. The prepared API dispersion was fed into a bead mill (Netzsch, MiniCer, bead size 0.5 mm) and a grinding process was performed at a speed of 2500 rpm. At this time, a primary coating solution was prepared by continuously stirring with an overhead stirrer during the pre-, mid-, and post-grinding processes.

[0293]

[0294] Formation of the primary coating layer

[0295] Inert particles (spherical sugar (45 / 60 mesh)) were introduced into a fluid bed granulator (FBG) and flowed, and the first coating solution prepared above was sprayed to form a first coating layer on the core surface, thereby producing a first coating product.

[0296] Fluidized bed granulator operating conditions

[0297] - Supply air temperature: 50 ℃

[0298] - Supply air volume: 75~110 m 3 / h

[0299] - Liquid volume: 4~8 g / min

[0300] - Atomizing / Microclimate air pressure: 0.8 / 0.05 bar

[0301]

[0302] Coating Pellet Manufacturing

[0303] A coating base (Eudragit E PO), a surfactant (sodium lauryl sulfate), and an emulsifier (stearic acid) were added to purified water and stirred with an overhead stirrer for 2 hours. Afterward, a lubricant (talc) was added and uniformly dispersed, and then filtered through a 0.5 mm sieve to prepare a secondary coating solution.

[0304] Next, the first coating material prepared above was introduced into a fluidized bed granulator and flowed, while spraying the second coating liquid prepared above to form a second coating layer on the surface of the first coating material, thereby producing a coating pellet.

[0305] Fluidized bed granulator operating conditions

[0306] - Supply air temperature: 30~35 ℃

[0307] - Supply air volume: 90 m 3 / h

[0308] - Liquid volume: 4~8 g / min

[0309] - Atomizing / Microclimate air pressure: 0.8 / 0.05 bar

[0310]

[0311] Mix after

[0312] Oral disintegrating tablets were prepared by adding the following mixture listed in Table 12 to the coated pellets after the second coating was completed, mixing, and compressing.

[0313]

[0314] Example 3-2

[0315] The procedure was carried out in the same manner as in Example 3-1, but without using a sweetener, a first coating solution was prepared, and then a first coating product was prepared.

[0316] Next, an orally disintegrating tablet was prepared in the same manner as in Example 3-1, except that each material was used in the amounts listed in Table 12 below during the preparation of the coating pellet and subsequent mixing.

[0317]

[0318] Example 3-3

[0319] The procedure was carried out in the same manner as in Example 3-2, but with the additional use of a surfactant (Polysorbate 80) and the use of Fexuprazan from Preparation Example 2 instead of Fexuprazan HCl as the API to prepare a first coating solution, and then a first coating product was prepared.

[0320] Next, an orally disintegrating tablet was prepared in the same manner as in Example 3-2, except that each material was used in the amounts listed in Table 12 below during the preparation of the coating pellet and subsequent mixing.

[0321]

[0322] Examples 3-4

[0323] The procedure was carried out in the same manner as in Example 3-2, but a primary coating solution was prepared using hydroxypropyl methylcellulose (3 mPas) as a binder, and a primary coating product was prepared.

[0324]

[0325] Coating Pellet Manufacturing

[0326] A coating agent (Eudragit E PO readymix) was added to purified water and vigorously stirred with an overhead stirrer to prepare a suspension. Afterward, the stirring speed was reduced to remove bubbles, a lubricant (talc) was added and uniformly dispersed, and then filtered through a 0.5 mm sieve to prepare a secondary coating solution.

[0327] Oral disintegrating tablets were prepared in the same manner as in Example 3-2, except that the above secondary coating solution was used when preparing the coating pellets, and each substance was used in the amounts listed in Table 12 below when mixing.

[0328]

[0329] Examples 3-5

[0330] Preparation of 1st coating solution

[0331] API (Fexuprazan HCl of Preparation Example 1) was ground twice using a Jet-mill (MV TECCH, grinding pressure 6 bar, input amount 100 g / 90 sec) to finely pulverize it, and then the finely pulverized API and a binder (Opadry 00K190000) were added to purified water and stirred with an overhead stirrer to prepare a first coating solution. Meanwhile, the particle size distribution before and after grinding the API is as shown in Table 11 below.

[0332] Oral disintegrating tablets were prepared in the same manner as in Examples 3-4, except that the above-mentioned first coating solution was used when forming the first coating layer, and each material was used in the amounts listed in Table 12 below when preparing the coating pellets and mixing thereafter.

[0333]

[0334] D 10 (㎛)D 50 (㎛)D 90 (㎛)D 99 (㎛) Before grinding 1.98 10.4 139.2 28 4.6 4 After 1st grinding 0.58 1.5 6 4.00 6.7 6 After 2nd grinding 0.55 1.2 32.98 4.5 2

[0335] The materials and amounts used in the above Examples 3-1 to 3-5 are summarized in Table 12 below.

[0336]

[0337] Process Formulation Purpose Ingredient Usage (Parts by Weight) Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 3-5 1st Coating Core Sugar Sphere (45 / 60 mesh) 125 125 125 125 API Fexuprazan HCl 100 100 -100 100 API Fexuprazan --91.85-- Surfactant Polysorbate 80 --1.25-- Binder Low-viscosity Hydroxypropyl Cellulose 12.5 12.5 12.5-- Binder Hydroxypropyl Methylcellulose (3mPas) ---25- Binder *Opadry 00K 190000----25 Sweetener Aspartame 12.5---- Solvent Purified Water 500 500 500 500 2nd Coating Coating Base Eudragit E PO 305 3.575 53.575 -- Coating Base Eudragit E PO Readymix --- 100 100 Surfactant Sodium Lauryl Sulfate 35.35 5.35 -- Emulsifier Stearic Acid 4.5 8.025 8.025 -- Lubricant Talc 15 26.8 26.8 2.5 2.5 Solvent Purified Water 297.55 31.275 531.275 400 455.55 Coating Pellet Weight (Parts by Weight) 302.5 331.25 324.35 352.5 352.5 After Mixture Excipient Mannitol and Starch Mixture (Pearlitol Flash) 652.5 438.75 445.65 417.5 417.5 Excipient Undetermined Cellulose-100100100100 Disintegrant Crospovidone-50505050 Sweetener Aspartame-2550505050 Lubricant Colloidal Silicon Dioxide-10101010 Colorant Green Colorant-1010101010 Flavoring Agent Peppermint Flavoring-55555 Lubricant Magnesium Stearate-55555 Total Weight (Parts by Weight) 100010001000100010001000 Based on 100 parts by weight of API Secondary Coating Layer Content (Parts by Weight) 52.593.75102102.5102.5 Based on Total Weight Coating Pellet Content (%) 3033323535

[0338] *Opadry 00K190000: Mixture of hydroxypropyl methylcellulose (3 mPas), triacetin, and talc

[0339] Experimental Example 4

[0340] Hardness and disintegration time were measured for the orally disintegrating tablets of Examples 3-1 to 3-5 above, and sensory evaluations were performed. The results are shown in Table 13 below. Hardness and sensory evaluations were conducted in the same manner as in Experimental Example 1 above, and disintegration time was evaluated according to the disintegration test method of the Korean Pharmacopoeia.

[0341]

[0342] Example 3-1 Example 3-2 Example 3-3 Example 3-4 Example 3-5 Hardness (KP) 7 10 8 6 6 Disintegration Time (sec) 12 17~19 2 115 ~ 2 3 17~30 Sensory Evaluation 0~30~10~10~10~1 Remarks Foreign Object Sensitivity X--- Abrasion 0.2~0.34%

[0343] As can be seen in Table 13 above, the oral disintegrating tablets of the examples were found to have excellent hardness, disintegration time, and sensory evaluation.

[0344]

[0345] Experimental Example 5

[0346] A comparative dissolution evaluation was conducted for the above Examples 3-4 with the reference drug (Comparative Example 1-1), and the results are shown in Table 14 below.

[0347] Comparative dissolution evaluation was performed in a pH 1.2 dissolution solution according to the comparative dissolution test method in Annex 5-2 of the Standards for Testing Pharmaceutical Equivalence of Drugs notified by the Ministry of Food and Drug Safety.

[0348]

[0349] Test Solution Classification Average Dissolution Rate (%) 5 min 10 min 15 min 30 min pH 1.2 Control Drug 66.5 81.2 84.2 86.9 Example 3-4 38.3 73.3 86.8 91.7

[0350] As can be seen in Table 14 above, the oral disintegrating tablets of Examples 3-4 showed a dissolution rate of 85% or more at 15 minutes in a pH 1.2 test solution, and it was confirmed that they had a dissolution profile equivalent to that of the control drug.

Claims

A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and granules comprising a pharmaceutically acceptable additive; A coating layer formed on the surface of the above granules and comprising a polymer-containing coating base; and including a post-mixture, Oral disintegrating tablet: [Chemical Formula 1] . In paragraph 1, The above pharmaceutically acceptable additive comprises one or more selected from the group consisting of excipients, lubricants, sweeteners, and binders, Oral disintegrating tablet. In paragraph 1, Comprising 30 to 95 weight percent of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof based on the total weight of the granules, Oral disintegrating tablet. In paragraph 1, The above polymer comprises one or more of (meth)acrylate-based polymers and alkylcellulose, and The above (meth)acrylate-based polymer is one or more of homopolymers and copolymers of one or more monomers selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid esters, alkyl (meth)acrylates, aminoalkyl (meth)acrylates, and ammonio(meth)acrylates, Oral disintegrating tablet. In paragraph 1, The above polymer comprises one or more selected from the group consisting of a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; a copolymer of methacrylic acid and ethyl acrylate; an ammoniomethacrylate copolymer; and ethylcellulose. Oral disintegrating tablet. In paragraph 1, The above coating layer further comprises one or more selected from the group consisting of surfactants, emulsifiers, and lubricants, Oral disintegrating tablet. In paragraph 1, The coating layer is included in an amount of 50 to 90 parts by weight based on 100 parts by weight of the granules, Oral disintegrating tablet. In paragraph 1, The above-mentioned mixture comprises one or more selected from the group consisting of excipients, disintegrants, sweeteners, flavorings, colorings, and lubricants, Oral disintegrating tablet. In paragraph 1, A mixture comprising 50 to 90 weight% based on the total weight of the orally disintegrating tablet, Oral disintegrating tablet. A core containing inert particles; A first coating layer formed on the above core and comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and A coating pellet comprising: a second coating layer formed on the first coating layer and comprising a polymer-containing coating base; Oral disintegrating tablet: [Chemical Formula 1] . In Paragraph 10, The above-mentioned inert particles comprise one or more selected from the group consisting of sucrose, microcrystalline cellulose, mannitol, sorbitol, microcrystalline wax, silicon dioxide, lactose monohydrate, and mixtures thereof, Oral disintegrating tablet. In Paragraph 10, Average particle size (D of the above core) 50 ) is 50 to 400 μm, Oral disintegrating tablet. In Paragraph 10, The first coating layer further comprises one or more selected from the group consisting of binders, surfactants, lubricants, and sweeteners, Oral disintegrating tablet. In Paragraph 10, The first coating layer comprises a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof with an average particle size (D 50 ) containing finely divided particles of 20 μm or less, Oral disintegrating tablet. In Paragraph 10, Average particle size (D of the core and the first coating layer) 50 ) is 100 to 450 μm, Oral disintegrating tablet. In Paragraph 10, The above polymer is one or more of homopolymers and copolymers of one or more monomers selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylates, aminoalkyl (meth)acrylates, (meth)acrylic acid esters, and ammonio(meth)acrylates. Oral disintegrating tablet. In Paragraph 10, The above polymer comprises one or more selected from the group consisting of a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; a copolymer of methacrylic acid and ethyl acrylate; and an ammoniomethacrylate copolymer. Oral disintegrating tablet. In Paragraph 10, The second coating layer further comprises one or more additives selected from the group consisting of surfactants, emulsifiers, and lubricants, Oral disintegrating tablet. In Paragraph 10, A second coating layer comprising 30 to 200 parts by weight based on 100 parts by weight of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, Oral disintegrating tablet. In Paragraph 10, Average particle size (D of the above coating pellets) 50 ) is 120 to 500 μm, Oral disintegrating tablet. In Paragraph 10, A further comprising a post-mixing agent comprising one or more selected from the group consisting of excipients, disintegrants, sweeteners, flavoring agents, coloring agents, and lubricants, Oral disintegrating tablet. In Paragraph 10, Based on the total weight of the orally disintegrating tablet, comprising 10 to 35 weight percent of coated pellets, Oral disintegrating tablet. A step of preparing a primary coating solution comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof (Step 1); A step of forming a first coating layer by coating the first coating solution onto a core containing inert particles using a fluid bed granulator (Step 2); and A method comprising the step (step 3) of manufacturing a coating pellet by forming a second coating layer by coating a coating composition containing a polymer-containing coating base onto the first coating layer, Method for manufacturing an orally disintegrating tablet: [Chemical Formula 1] . In Paragraph 23, The primary coating solution of Step 1 above is, A compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof; One or more selected from the group consisting of binders, surfactants, sweeteners, and lubricants; and A mixture containing a solvent, Method for manufacturing an orally disintegrating tablet. In paragraph 24, The above mixture is a suspension, and comprises the step of preparing the above suspension into finely divided particles of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof through a wet grinding process using a bead mill, Method for manufacturing an orally disintegrating tablet. In paragraph 25, Average particle size (D) of the above-mentioned finely divided particles 50 ) is 20 µm or less, Method for manufacturing an orally disintegrating tablet. In paragraph 24, A compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is ground to produce finely pulverized particles, and A method comprising the step of preparing a mixture by mixing the above-mentioned finely divided particles with one or more selected from the group consisting of a binder, a surfactant, and a lubricant; and a solvent. Method for manufacturing an orally disintegrating tablet. In paragraph 27, Average particle size (D) of the above-mentioned finely divided particles 50 ) is 20 µm or less, Method for manufacturing an orally disintegrating tablet. In Paragraph 23, A step of mixing the coating pellet with one or more post-mixing agents selected from the group consisting of excipients, disintegrants, sweeteners, flavoring agents, coloring agents, and lubricants (Step 4); and Further comprising the step of tableting the mixture of step 4 above (step 5); Method for manufacturing an orally disintegrating tablet.

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