1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine-ion exchange resin complex, orally disintegrating tablet comprising the same, and method for preparing the same

Abstract

The present invention relates to a 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine-ion exchange resin complex having excellent dissolution characteristics and taste shielding properties, and an orally disintegrating tablet containing the same.

Description

Technology Field

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

[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.

[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.

[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.

[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.

[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.

[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.

[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, the present invention was completed by developing a drug-ion exchange resin composite and an oral disintegrating tablet that have excellent dissolution characteristics and a bitter taste masking effect by applying an ion exchange resin. The problem to be solved

[0017] The present invention is to provide an ion exchange resin complex 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 an orally disintegrating tablet and a method for manufacturing the same. means of solving the problem

[0019] To solve the above problem, the present invention provides a drug-ion exchange resin complex in which a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and a cation exchange resin are chemically bonded, wherein the complex comprises 30 to 250 parts by weight of the cation exchange resin based on 100 parts by weight of the compound represented by the chemical formula 1 or the pharmaceutically acceptable salt thereof:

[0020] [Chemical Formula 1]

[0021] .

[0023] In addition, the present invention provides an orally disintegrating tablet comprising the above-mentioned drug-ion exchange resin complex.

[0025] In addition, the present invention provides a method for manufacturing an orally disintegrating tablet, comprising the steps of: preparing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; preparing a solution by dissolving the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a solvent; and adding a cation exchange resin to the solution to induce an ion exchange reaction with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to form a complex, and further comprising the step of preparing a drug-ion exchange resin complex by reacting the cation exchange resin in an amount of 30 to 250 parts by weight based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0027] Meanwhile, in this specification, “drug-ion exchange resin complex” means a complex formed by chemically bonding a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; and a cation exchange resin. Additionally, unless otherwise noted, “complex” means the “drug-ion exchange resin complex.”

[0029] 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.

[0031] 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.

[0033] 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.

[0035] 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.

[0037] 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.

[0039] In the present invention, the invention was completed by confirming that a drug-ion exchange resin complex, in which a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is reacted in a certain ratio with a cationic ion exchange resin and chemically bonded, can block the expression of a bitter taste of the drug in the oral cavity, and that an orally disintegrating tablet containing the same also exhibits excellent bitter taste shielding and excellent dissolution characteristics in the gastrointestinal environment.

[0041] In the drug-ion exchange resin composite according to the present invention, the cation exchange resin is a material that forms a complex chemically bonded with a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. The cation exchange resin is a material having a structure in which a negatively charged ion exchange group is bonded to an insoluble organic or inorganic polymer matrix, and the chemical bond refers to an ionic bond due to the characteristics of the ion exchange resin, and is not limited to any type as long as it is capable of forming an ionic bond.

[0042] Specifically, the cation exchange resin contains acidic functional groups within the resin, and the acidic functional groups are bonded by electrostatic attraction to the basic portion (e.g., amine group or ammonium cation) of a compound represented by Formula 1 in an aqueous solution or a suitable solvent system. At this time, the cation exchange resin may include both strong acidic cation exchange resins and weak acidic cation exchange resins depending on the degree of dissociation of the functional groups, and these may be based on cross-linked styrene, acrylic acid, or methacrylic acid-based polymers.

[0043] In the process of forming the complex of the present invention, the compound represented by Formula 1 is substituted with the counter ion of the cation exchange resin and immobilized inside or on the surface of the resin matrix. This ion exchange reaction is carried out through a reversible equilibrium reaction, and the formed complex can suppress the rapid release of the drug in the oral environment, thereby effectively shielding the characteristic bitter taste of the compound represented by Formula 1 or its pharmaceutically acceptable salt and promoting the chemical stability of the formulation.

[0045] The above cation exchange resin may be used without particular limitation as long as it does not have a negative effect on the pharmaceutical activity of the compound represented by Chemical Formula 1 or its salt. The above cation exchange resin may be a weak acid cation exchange resin, a strong acid cation exchange resin, etc., and may include carboxylic acid and / or sulfonic acid as functional groups within the ion exchange resin. Depending on the type of monomer of the above cation exchange resin, examples include a cross-linked polymer of methacrylic acid and divinylbenzene, a cross-linked polymer of styrene sulfonic acid and divinylbenzene, or a cross-linked polymer of styrene and divinylbenzene.

[0047] Preferably, the cation exchange resin may be a polymer containing carboxyl groups or a salt thereof. More preferably, it may be a copolymer of methacrylic acid and divinylbenzene or a salt thereof. When the cation exchange resin exists in the form of a salt, the types of cations present in the resin are not particularly limited, but H + , Na + , K + There may be others. Specifically, the cation exchange resin may be polycrilin potassium (product name: Amberlite IRP 88).

[0049] Meanwhile, the drug-ion exchange resin complex of the present invention comprises 30 to 250 parts by weight of the cation exchange resin based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. By reacting the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof with the cation exchange resin to form a complex within the above weight ratio range, it is possible to secure pharmaceutical properties that are effective for taste masking, exhibit excellent dissolution characteristics, and are easy to store and distribute.

[0050] More specifically, based on 100 parts by weight of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, the cation exchange resin may be included in an amount of 35 parts by weight or more, 40 parts by weight or more, 45 parts by weight or more, or 50 parts by weight or more, and 250 parts by weight or less, 240 parts by weight or less, 230 parts by weight or less, 220 parts by weight or less, 210 parts by weight or less, 200 parts by weight or less, 190 parts by weight or less, 180 parts by weight or less, 170 parts by weight or less, 160 parts by weight or less, 150 parts by weight or less, 145 parts by weight or less, 140 parts by weight or less, 135 parts by weight or less, 130 parts by weight or less, 125 parts by weight or less, or 120 parts by weight or less.

[0051] Preferably, the complex may comprise 80 to 120 parts by weight, 85 to 110 parts by weight, or 90 to 100 parts by weight of the cation exchange resin based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0053] Meanwhile, the average particle size (D) of the above composite 50 ) may be 100 µm or less. Since orally disintegrating tablets must disintegrate rapidly in the oral cavity by a small amount of saliva, the particle size felt after disintegration has a decisive influence on the texture. If the average particle size of the complex exceeds 100 µm, grittiness and a rough texture caused by residual particles in the oral cavity may be induced, potentially leading to patient aversion to taking the medication. Specifically, the average particle size (D) of the complex 50 The particle size may be 97 μm or less, 95 μm or less, 93 μm or less, or 90 μm or less. Meanwhile, the lower limit of the average particle size of the composite is not specifically limited, but may be, for example, 1 μm or more, 5 μm or more, 10 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, or 30 μm or more.

[0055] In addition, the particle size (D) of the above composite 90 ) may be 200 µm or less. Particle size corresponding to the top 10% of the particle size distribution (D 90 When ) is 250 μm or less, a foreign body sensation in the oral cavity caused by relatively large particles can be prevented. Preferably, the particle size (D) of the composite is 90 ) may be 230 µm or less, 200 µm or less, 190 µm or less, 180 µm or less, or 175 µm or less. D 90 If the value exceeds the above range and contains a large number of large particles, the average particle size (D 50 Even if ) satisfies 100 μm or less, it is difficult to eliminate the foreign body sensation in the oral cavity. Meanwhile, the particle size (D) of the above composite 90 The lower limit is not specifically restricted, but may be, for example, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 110 μm or more, or 120 μm or more.

[0057] Here, the above "particle size (D X The 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 size (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 diameter of the particle 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.

[0059] At this time, the particle size (D) of the drug-ion exchange resin complex formed from the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof; and the cation exchange resin 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.

[0061] The measurement of the volume-average particle size distribution of a drug-ion exchange resin composite by such laser diffraction 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.

[0063] In addition, the drug-ion exchange resin composite according to the present invention may exhibit a dissolution rate of 80% or more, 83% or more, 85% or more, 87% or more, 90% or more, or 93% or more within 15 minutes as measured by the dissolution test method No. 2 (Paddle Method) of the Korean Pharmacopoeia. At this time, the upper limit of the dissolution rate within 15 minutes is not specifically limited, but may be 100% or less, 99% or less, 98% or less, or 97% or less. The measurement of the above dissolution rate may be specified in the examples described later.

[0065] Meanwhile, an Electronic Tongue System may be used to objectively evaluate the taste-masking performance of the drug-ion exchange resin composite according to the present invention and the orally disintegrating tablet containing the same. The Electronic Tongue System mimics the biological mechanism in which microcells present in human lingual papillae detect taste components, and detects taste components through a Lipid / Polymer Membrane Sensor.

[0066] Each sensor causes a change in the potential of the sensor membrane through electrostatic interaction or hydrophobic interaction with taste-inducing components in the sample, and the amount of the change in potential (mV) is correlated with the concentration of taste components remaining in the sample. In the present invention, the α-Astree system of Alpha MOS can be used, which is equipped with a dedicated sensor for detecting sourness (CA0), bitterness (CO0, AN0, BT0), sweetness (GL1), umami (AAE), saltiness (CT0), etc., to collect the gustatory profile of each sample.

[0068] High-dimensional potential difference data collected from multiple sensors is dimensionally reduced through Principal Component Analysis (PCA), a multivariate statistical analysis technique. PCA is a technique that transforms data into independent principal components (PC) while preserving the variance of the data as much as possible, which allows high-dimensional taste data to be visualized as data points on a 2D or 3D coordinate system.

[0070] On the PCA map, the distance between data points of each sample represents taste similarity. In other words, the closer the points of specific samples are located to each other, the more similar their taste patterns are; conversely, the further apart they are located, the more different their taste characteristics are. For example, the degree of masking is determined through the relative positional relationship between a cluster of active ingredients with a bitter taste and a cluster of tasteless placebos. That is, if a data point is located far from the active ingredient cluster and adjacent to the tasteless cluster, it means that the drug's inherent bitter taste has been successfully masked.

[0072] In addition, the taste masking degree can be quantified as a relative value by calculating the Euclidean distance, which is the geometric distance between each cluster in the PCA coordinate system. For example, compared to the Euclidean distance value between a bitter-tasting sample and a tasteless cluster, the smaller the distance value between the complex according to the embodiment of the present invention and the tasteless cluster, that is, the closer the distance to the tasteless cluster, the better the taste-masking efficiency can be determined.

[0074] Meanwhile, the present invention provides an orally disintegrating tablet comprising the above-mentioned drug-ion exchange resin complex.

[0076] Additionally, the complex may be included in an amount of 10 to 50 weight% based on the total weight of the orally disintegrating tablet. If the complex content is less than 10 weight%, the size of the orally disintegrating tablet may become excessively large, and if it exceeds 50 weight%, problems may occur during tablet compression due to increased viscosity and volume, or the dissolution rate may decrease due to a decrease in the proportion of water-soluble excipients. Preferably, the complex may be included in an amount of 10 to 45 weight%, 10 to 40 weight%, 10 to 35 weight%, 10 to 25 weight%, or 10 to 20 weight% based on the total weight of the orally disintegrating tablet.

[0078] Meanwhile, the oral disintegrating tablet may further include one or more additives selected from the group consisting of excipients, disintegrants, sweeteners, flavorings, lubricants, and colorings. More specifically, the oral disintegrating tablet may further include an excipient; and one or more additives selected from the group consisting of disintegrants, sweeteners, flavorings, lubricants, and colorings.

[0080] Specifically, the orally disintegrating tablet according to the present invention may further include excipients. Here, “excipient” refers to a pharmaceutically acceptable ingredient used to form a product shape that facilitates the administration of the active ingredient exhibiting the pharmacological effect of the orally disintegrating tablet of the present invention. Commonly used excipients include microcrystalline cellulose, lactose monohydrate, sucrose, D-mannitol, starch, corn starch, and hard anhydrous silica, and the orally disintegrating tablet may include commonly used excipients without limitation. However, in terms of improving the dissolution characteristics of the active ingredient, the orally disintegrating tablet may include a combination of two types of excipients, mannitol and microcrystalline cellulose, in a specific weight ratio. This can be confirmed in the examples to be described later.

[0082] Specifically, the orally disintegrating tablet according to the present invention further comprises an excipient; said excipient may be a mixture of mannitol and microcrystalline cellulose mixed in a weight ratio of 5:1 to 1:5. Preferably, said excipient may be a mixture of mannitol and microcrystalline cellulose mixed in a weight ratio of 4:1 to 1:4 or 3:1 to 1:3. If the proportion of mannitol is excessive, the oral cooling sensation is excellent, but the hardness of the tablet decreases, increasing abrasion and posing a risk of breakage during storage. Conversely, if the proportion of microcrystalline cellulose is excessive, a problem may arise in which the disintegration time is delayed due to the pressure of tablet compression.

[0084] Additionally, specifically, the orally disintegrating tablet according to the present invention may contain the excipient in an amount of 55 to 85 weight% based on the total weight of the orally disintegrating tablet. Preferably, based on the total weight of the orally disintegrating tablet, the excipient may be contained in an amount of 60 weight% or more, 65 weight% or more, 70 weight% or more, or 75 weight% or more and 85 weight% or less, or 83 weight% or less. If the content of the excipient is less than 55 weight%, the proportion of the drug-ion exchange resin complex in the total volume of the tablet becomes relatively high, resulting in insufficient binding strength during tablet compression, which may cause problems such as a decrease in tablet hardness or an increase in abrasion. On the other hand, if the content of the excipient exceeds 85 weight%, the wetting and disintegration speed by saliva may be significantly delayed due to the increase in the total volume of the tablet, and the quality of administration characteristic of orally disintegrating tablets is degraded, such as by causing grittiness due to an increased amount of powder remaining in the oral cavity. Furthermore, as the dilution ratio of the active ingredient within the unit formulation becomes excessively high, it becomes difficult to ensure uniform mixing during the manufacturing process and increases packaging and logistics costs, which becomes a factor that hinders marketability from an industrial perspective.

[0086] In addition, the oral disintegrating tablet of the present invention may further include a disintegrating agent, a binder, a sweetener, a flavoring agent, a lubricant, a coloring agent, a stabilizer, etc., in addition to the above excipients.

[0088] The above disintegrant may include sodium croscarmellose, granulated powder mannitol, crospovidone, calcium carboxymethylcellulose, sodium starch glycolate, or starch. In this case, it is preferable to use one or more of the disintegrants selected from the group consisting of sodium croscarmellose, calcium carboxymethylcellulose, and sodium starch glycolate, in order to further improve storage stability without causing a decrease in dissolution rate and content under conditions similar to the gastrointestinal environment of the body.

[0090] The above lubricant is added to increase the fillability of the formulation and facilitate compression. One or more of stearic acid, magnesium stearate, 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, magnesium stearate is used as the lubricant for ease of the manufacturing process.

[0092] The above binder is added to maintain the form of the formulation, and the binder may include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silicon dioxide, mannitol, lactose, polyethylene glycol, and mixtures thereof, but is not limited thereto.

[0094] In addition, titanium oxide, yellow iron oxide, red iron oxide, black iron oxide, titanium dioxide, talc, etc., may be used as the coloring agent, but are not limited thereto. Preferably, for aesthetic purposes, yellow iron oxide is used as the coloring agent.

[0096] In addition, the oral disintegrating tablet of the present invention may comprise, based on the total weight of the oral disintegrating tablet, 10 to 30 weight% of a complex chemically bonded to a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a cation exchange resin; 55 to 85 weight% of an excipient comprising mannitol and microcrystalline cellulose; 1 to 15 weight% of a disintegrant; and 0.1 to 5 weight% of a lubricant.

[0098] In addition, the orally disintegrating tablet according to the present invention is in accordance with the United States Pharmacopoeia (USP). <701> When measured according to the disintegration test method, it can disintegrate within 30 seconds, which is the U.S. Food and Drug Administration (FDA) recommended standard for orally disintegrating tablets. Having a disintegration time within the above range can improve compliance and adequately maintain the masking of bitter taste.

[0100] Meanwhile, the present invention provides a method for manufacturing an orally disintegrating tablet, comprising the steps of: preparing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; preparing a solution by dissolving the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in a solvent; and adding a cation exchange resin to the solution to induce an ion exchange reaction with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to form a complex, and further comprising the step of preparing a drug-ion exchange resin complex by reacting 30 to 250 parts by weight of the cation exchange resin based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0102] At this time, the description of the compound represented by Chemical Formula 1 or its pharmaceutically acceptable salt, cation exchange resin, and complex is as described above.

[0104] Meanwhile, in the above solution preparation step, the solvent is not particularly limited as long as it is a substance capable of dissolving a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and may be, for example, water.

[0106] Additionally, the above ion exchange reaction may be carried out at 40°C to 60°C. Carrying out the reaction at a temperature within this range is suitable for the ion exchange reaction between the compound represented by Formula 1 or its pharmaceutically acceptable salt and the cation exchange resin. Specifically, if the temperature is below 40°C, the rate of the ionic bonding reaction becomes excessively slow, and if it exceeds 60°C, the amount of the active ingredient may increase. Preferably, the above ion exchange reaction may be carried out at 45°C to 55°C, or at 50°C.

[0108] In addition, when manufacturing the orally disintegrating tablet of the present invention, the complex can be compressed by the direct compression method to produce the orally disintegrating tablet. When the direct compression method is applied in the manufacturing process of the orally disintegrating tablet, it is advantageous to preserve the stability of the compound represented by Chemical Formula 1, which is sensitive to moisture or heat, or its pharmaceutically acceptable salt, and economic efficiency can be secured through process simplification, and content uniformity of the active ingredient in the orally disintegrating tablet can be secured.

[0110] Meanwhile, when manufacturing an orally disintegrating tablet by direct compression, the compression pressure is not particularly limited, but may be 10 kN to 20 kN, and specifically may be 10 kN, 11 kN, 12 kN, 13 kN, 14 kN, or 15 kN.

[0112] 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.

[0114] 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. Effects of the invention

[0116] As described above, the 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine-ion exchange resin complex of the present invention can be used as an orally disintegrating tablet useful for gastroesophageal reflux disease by including each component in the complex in a specific weight ratio, thereby having excellent dissolution characteristics and taste shielding properties. Brief explanation of the drawing

[0118] Figure 1 is a scanning electron microscope / energy dispersive X-ray detector spectroscopy image of the API of Preparation Example 1, cation exchange resin (Amberlite™ IRP 88 (Dupont)), Comparative Example 1-1, and Example 1-1. FIG. 2 is a Fourier transform infrared spectroscopic analysis graph of the API of Preparation Example 1, Fexuprazan of Preparation Example 2, cation exchange resin (Amberlite™ IRP 88 (Dupont)), Comparative Examples 1-1 to 1-3, and Examples 1-1 to 1-3. FIG. 3 shows the API of Preparation Example 1, Fexuprazan of Preparation Example 2, Comparative Examples 1-2, and Examples 1-2. 15 This is a graph of N solid-state nuclear magnetic resonance spectroscopy analysis. Figure 4 is a PCA (Principal component anylasis) map graph using the electronic tongue system of Examples 1-1 to 1-3. Figure 5 is a PCA (Principal component analysis) map graph using an electronic tongue system of cation exchange resin (Amberlite™ IRP 88 (Dupont), Comparative Example 1, Example 1-1 and Example 2-6). Specific details for implementing the invention

[0119] 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.

[0121] Preparation Example 1

[0122] The hydrochloride salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine, which is the main component represented by the above chemical formula 1 (hereinafter abbreviated as API (active pharmaceutical ingredients)), was prepared by the method described in the example of Korean Patent Registration No. 10-2126576.

[0124] Preparation Example 2

[0125] 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.

[0127] Example 1-1

[0128] 400 mL of distilled water was added to a glass beaker and heated and maintained at 50 ℃. 100 parts by weight of the API prepared above were added to this, and the solution was stirred sufficiently until it became transparent to completely dissolve the drug. After visually confirming that the drug was completely dissolved, 100 parts by weight of a cross-linked polymer cation exchange resin of methacrylic acid and divinylbenzene (Amberlite™ IRP 88 (Dupont)) was added based on 100 parts by weight of the API. Subsequently, the mixture was stirred at a speed of 200 rpm for a certain period of time to induce a complex formation reaction through ionic bonding between the API and the ion exchange resin.

[0130] To determine the drug loading profile and the time to reach equilibrium, 0.2 mL of the reaction solution was taken at 5, 10, 15, 30, 45, 60, 90, and 120 minutes, starting immediately after the addition of the ion exchange resin (0 min). The collected samples were placed in e-tubes and centrifuged at 15,000 rpm for 5 minutes, after which only the supernatant was collected. The separated supernatant was diluted with an equal amount of methanol, and the residual drug concentration was measured using HPLC (High Performance Liquid Chromatography) to calculate the drug loading rate over time.

[0132] After the reaction was completed, the drug-resin suspension was filtered under reduced pressure using a filtration device equipped with a microfiber filter. The drug-ion exchange resin composite obtained through filtration was sufficiently dried for 12 hours in a convection oven set to 50°C to remove residual moisture. After drying, the composite lumps were uniformly ground using a grinding device (such as a mortar and pestle) and then passed through a No. 45 sieve (ASTM mesh No. 45, aperture approximately 355 μm) to select only the composite powder with a uniform particle size, thereby preparing the drug-ion exchange resin composite.

[0134] Examples 1-2

[0135] A drug-ion exchange resin complex was prepared in the same manner as in Example 1-1, except that 50 parts by weight of cationic ion exchange resin was added based on 100 parts by weight of API.

[0137] Examples 1-3

[0138] A drug-ion exchange resin complex was prepared in the same manner as in Example 1-1, except that 200 parts by weight of cationic ion exchange resin was added based on 100 parts by weight of API.

[0140] Comparative Example 1-1

[0141] A physical mixture was prepared by weighing 100 parts by weight of cationic ion exchange resin (Amberlite™ IRP 88 (Dupont)) to 100 parts by weight of the API prepared in Preparation Example 1 above and mixing them in a simple mixing manner.

[0143] Comparative Example 1-2

[0144] A physical mixture was prepared by weighing 50 parts by weight of a cationic ion exchange resin (Amberlite™ IRP 88 (Dupont)) to 100 parts by weight of the API prepared in Preparation Example 1 above and mixing them in a simple mixing manner.

[0146] Comparative Examples 1-3

[0147] A physical mixture was prepared by weighing 200 parts by weight of cationic ion exchange resin (Amberlite™ IRP 88 (Dupont)) to 100 parts by weight of the API prepared in Preparation Example 1 above and mixing them in a simple mixing manner.

[0149] Experimental Example 1-1: Particle Size Analysis

[0150] For the drug-ion exchange resin composites prepared in Examples 1-1 to 1-3 above, the particle size was evaluated using a laser diffraction analyzer (Mastersizer 2000, Malvern Instruments, UK) equipped with a dry powder separation unit (Scirocco 2000, Malvern, UK), and the results are shown in Table 1 below.

[0152] Parts by weight of ion exchange resin based on 100 parts by weight of API D 10 (μm) D 50 (μm) D 90 (μm) Example 1-1 100 30.641 77.413 132.832 Examples 1-2 50 19.088 87.502 173.492 Examples 1-3 200 31.123 71.582 125.536

[0153] As can be seen in Table 1 above, the drug-ion exchange resin composites of Examples 1-1 to 1-3 have an average particle size (D 50 ) is 100 μm or less, and the particle size (D 90 The particle size was 200 μm or less, which was a level that could prevent a foreign body sensation (sandy sensation) in the oral cavity when applied as an oral disintegrating tablet.

[0155] Experimental Example 1-2: Confirmation of Complex Formation

[0156] (1) Scanning electron microscope / energy dispersive X-ray detection spectroscopy analysis (SEM / EDS)

[0157] The API of Preparation Example 1, the cation exchange resin (Amberlite™ IRP 88 (Dupont)), the physical mixture of Comparative Example 1-1, and the drug-ion exchange resin composite prepared in Example 1-1 were analyzed using a scanning electron microscope and an energy-dispersive X-ray detection spectrometer (SEM-EDS, JSM-6010 plus LA, JEOL, Japan), and the results are shown in Figure 1. At this time, EDS mapping for the S element and the Cl element was performed for each sample.

[0159] Referring to Fig. 1, the S element included in the API in Comparative Example 1-1 and Example 1-1 could be identified. Meanwhile, the Cl element constituting the hydrochloric acid salt was identified in Comparative Example 1-1, whereas the Cl element was not identified in Example 1-1. Through this, unlike the physical mixture of the Comparative Example, the Cl of the API in the drug-ion exchange resin composite of the Example - It was confirmed that the ions dissociate and react with the carboxyl ions of the ion exchange resin to form ionic bonds.

[0161] (2) Fourier transform infrared spectroscopy (FT-IR)

[0162] Fourier transform infrared spectroscopy (IRTracer-100, Shimadzu, Japan) was performed on the API of Preparation Example 1, Fexuprazan of Preparation Example 2, cation exchange resin (Amberlite™ IRP 88 (Dupont)), Comparative Examples 1-1 to 1-3, and the drug-ion exchange resin complexes prepared in Examples 1-1 to 1-3. At this time, KBr pellets were prepared, and the spectral range was 400–4000 cm⁻¹. -1 The section is 4 cm -1 Analysis was performed by injecting a total of 32 times at the resolution, and the results are shown in Figure 2.

[0164] Referring to Fig. 2, the peak corresponding to the stretching of the ammonium ion of API is at 2436 cm⁻¹. -1 It could be observed in the vicinity, and in the case of the physical mixtures of Comparative Examples 1-1 to 1-3, a peak could be identified at the same position as API. On the other hand, in the case of the drug-ion exchange resin complex of the example, it could be confirmed that the corresponding peak disappeared, and it could be confirmed that the API and the ion exchange resin formed an ionic bond.

[0166] (3) 15 N Solid-state Nuclear Magnetic Resonance Spectroscopic Analysis ( 15 N Solid-state NMR spectroscopy)

[0167] With respect to the API of Preparation Example 1, Fexuprazan of Preparation Example 2, the physical mixture of Comparative Examples 1-2, and the drug-ion exchange resin complex prepared in Examples 1-2, 15 Solid-state nuclear magnetic resonance spectroscopy (Avance III HD, Bruker, Germany) was performed. For the analysis, a 4 mm probe was used, and the frequency was set to 40.560 MHz, pulse length to 4 μs, rotation speed to 10 kHz, and repetition delay to 5 seconds. Ammonium chloride (NH4Cl) powder was used as the standard material. The measurement results are shown in Figure 3.

[0169] Referring to Fig. 3, a peak corresponding to the pyrrole structure of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine was commonly observed around 140 ppm in all measured samples, confirming that the basic framework of the drug was maintained. Meanwhile, regarding the peak corresponding to the secondary ammonium ion, the API of Preparation Example 1 appeared at 6.98 ppm and the free base (salt-free) of Preparation Example 2 appeared at -19.98 ppm, whereas the drug-ion exchange resin complex of the Example showed a peak at -1.84 ppm. Furthermore, the physical mixture of the Comparative Example did not show a change in chemical displacement at the peak position of the API.

[0170] Through this, it was confirmed that the drug-ion exchange resin complex formed an ionic bond with the API through an ion exchange reaction with the ion exchange resin.

[0172] Experimental Examples 1-3: In vitro drug release evaluation

[0173] To evaluate the drug release behavior of the drug-ion exchange resin complexes of Examples 1-1 to 1-3 above, a dissolution test was performed according to Method 2 (Paddle Method) of the Korean Pharmacopoeia Dissolution Test Method.

[0174] Each complex in an amount equivalent to 40 mg of API was added to 900 mL of disintegration test solution 1 (pH 1.2), which was the dissolution solution, and the test was conducted at a temperature of 37±0.5℃ and a stirring speed of 50 rpm.

[0175] 5 mL of the eluent was taken at 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of elution, and filtered through a 0.45 μm PVDF syringe filter. During filtration, the initial 2 mL was discarded, the subsequent 1 mL was used as the test solution, and the remaining 2 mL was refluxed back into the vessel. To compensate for the reduced eluent volume due to sample collection, 3 mL of fresh Solution 1 was immediately added. The collected test solutions were diluted with methanol at a 1:1 (v / v) ratio, and the drug concentration was analyzed using an HPLC system. The cumulative drug release rate (%) over time is shown in Table 2 below.

[0177] Hours (minutes) Example 1-1 Examples 1-2 Examples 1-3 5 88.51 93.72 86.90 10 92.30 96.83 91.02 15 96.51 98.75 94.79 30 99.56 100.76 96.85 45 100.33 99.99 97.96 60 101.40 99.75 98.07 90 100.03 100.87 98.86 120 100.24 99.16 97.69

[0178] As can be seen in Table 2 above, the drug-ion exchange resin composite of the present invention exhibited excellent dissolution characteristics in which more than 90% of the drug was released within 15 minutes of the start of dissolution.

[0180] Experimental Examples 1-4: In vitro evaluation of taste masking

[0181] Taste masking was analyzed for the oral disintegrating tablets of Examples 1-1 to 1-3 using an electronic tongue system (α-Astree, Alpha MOS, France).

[0183] (1) Preparation of standard solution and test solution

[0184] Standard solution: Aqueous solutions with concentrations of 50, 100, 200, 400, and 800 μg / mL were prepared by dissolving the hydrochloride of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine in purified water (represented as “FPH 50 μg / mL”, “FPH 100 μg / mL”, “FPH 200 μg / mL”, “FPH 400 μg / mL”, and “FPH 800 μg / mL”, respectively), and 100 mL of the filtered solution was used after using a 0.45 μm PVDF syringe filter.

[0185] Test solution: The drug-ion exchange resin complex of Example 1-1 and the oral disintegrating tablet of Example 2-6 were each added to 200 mL of purified water and stirred for 1 minute, and then 100 mL of the filtered solution was used using a 0.45 μm PVDF syringe filter.

[0187] (2) Analysis and data processing

[0188] Each sample was analyzed six times for 2 minutes, and the collected electrical signal data was subjected to Principal Component Analysis (PCA) using dedicated software (Alpha soft V 16.0), and the results are shown in Fig. 4. In addition, the geometric distance between the standard solution and the example was measured, and the results are shown in Table 3.

[0190] division Geometric distance on a PCA map Examples 1-3 Example 1-1 Examples 1-2 FPH 50 μg / mL 7357.33 5886.10 2685.89 FPH 100 μg / mL 7739.56 6283.49 3154.52 FPH 200 μg / mL 8087.99 6659.02 3640.37 FPH 400 μg / mL 8499.26 7099.40 4182.71 FPH 800 μg / mL 9026.43 7654.63 4819.07

[0191] Referring to Fig. 4, it was confirmed that the drug-ion exchange resin complex according to the present invention is located on the left side, distinguished from the standard solutions, on the PCA map.

[0192] In addition, as can be seen from Table 3, when comparing the geometric distance between the drug-ion exchange resin complex of the example and the standard solution sample on the PCA map, it was confirmed that the drug-ion exchange resin complex shields the bitter taste of API by showing that the geometric distance increases as the concentration of the standard solution increases.

[0194] Examples 2-1 to 2-7

[0195] Oral disintegrating tablets were prepared using the drug-ion exchange resin complex prepared in Examples 1-1 to 1-3 above, D-mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate in the amounts listed in Table 4 below. At this time, with the total weight of the oral disintegrating tablet set to 400 mg, the content of the drug-ion exchange resin complex was determined so that the tablet could contain a drug-ion exchange resin complex equivalent to 40 mg of API.

[0197] Specifically, a drug-ion exchange resin complex, D-mannitol, microcrystalline cellulose, and crospovidone were added in predetermined amounts to a 3D shaker mixer (3D shaker mixer, Turbula® T2F mixer, Willy A. Bachofen AG, Switzerland). Subsequently, the mixture was mixed at a speed of 49 rpm for 5 minutes to obtain a homogeneous mixture. Magnesium stearate, a lubricant, was added to the mixture, and further mixed to prepare a final mixture.

[0199] The final mixture was used to manufacture orally disintegrating tablets by direct compression using a compaction simulator (Styl'One evolution, Medelpharm, France) equipped with a Euro-B type 11.28 mm flat-faced round punch and die set at a compression pressure of 15 kN and a compression speed of 15 rpm.

[0201] ingredient Example 2-1 Example 2-2 Examples 2-3 Examples 2-4 Examples 2-5 Examples 2-6 Examples 2-7 Drug-ion exchange resin complex 1) (g) Examples 1-3 134.14 134.14 134.14 - - - - Example 1-1 - - - 70.71 70.71 - - Examples 1-2 - - - - - 50.52 50.52 D-Mannitol (g) 182.9 121.93 60.97 153.65 76.82 245.61 163.74 Microcrystalline cellulose (g) 60.97 121.93 182.9 153.65 230.47 81.87 163.74 Crospovidone (g) 20 20 20 20 20 20 20 Magnesium stearate (g) 2 2 2 2 2 2 2 Total amount (g) 400.01 400 400.01 400.01 400 400 400 Drug-ion exchange resin complex content (weight%) based on total weight of orally disintegrating tablets 33.5 33.5 33.5 17.7 17.7 12.6 12.6 D-Mannitol: Microcrystalline Cellulose Weight Ratio 3:1 1:1 1:3 1:1 1:3 3:1 1:1 Content of excipients (D-mannitol and microcrystalline cellulose) based on total weight of orally disintegrating tablets (weight%) 61.0 61.0 61.0 76.8 76.8 81.9 81.9

[0202] 1) Weight of the drug-ion exchange resin complex corresponding to API 40 mg

[0203] Experimental Example 2-1: Evaluation of Disintegration Time

[0204] In order to simulate the oral disintegration behavior of the oral disintegrating tablets of Examples 2-1 to 2-7 above, an experiment was performed by equipping a physical property measuring instrument (TA.XT Plus, Stable Micro Systems, UK) with a dedicated tablet disintegration rig.

[0205] Specifically, an orally disintegrating tablet was attached to the tip of the probe using double-sided tape, and then lowered into a vessel containing 5 mL of purified water at 37 ℃. The experiment was performed in 'measure force in compression' mode, with the trigger force set to 10 g and the test speed set to 3.0 mm / sec.

[0206] The time-versus-disintegration curve of the probe during the disintegration process was recorded using Exponent software (Version 6.1.14.0). The disintegration time was calculated by extrapolating the point where the slope of the 'descending region,' where the probe descends as the drug disintegrates, meets the slope of the 'plateau region,' where movement stops upon completion of disintegration, and the results are shown in Table 5 below.

[0208] Disintegration time (sec) Example 2-1 20.12 Example 2-2 15.93 Examples 2-3 12.82 Examples 2-4 27.30 Examples 2-5 25.43 Examples 2-6 28.90 Examples 2-7 27.86

[0209] As can be seen in Table 5 above, it was confirmed that the orally disintegrating tablet according to the present invention has a disintegration time of within 30 seconds, which is suitable for use as an orally disintegrating tablet.

[0211] Experimental Example 2-2: In vitro drug release evaluation

[0212] For the orally disintegrating tablets of Examples 2-5, drug release was evaluated using the following method, and the results are shown in Table 6 below.

[0213] Evaluation was conducted using the paddle method (Apparatus 2) with a dissolution tester (Vision Classic 6, Hanson, USA).

[0214] 900 mL of disintegration test solution 1 (pH 1.2) was used as the eluent, and the temperature was maintained at 37°C with a stirring speed set to 50 rpm. At 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of elution, 5 mL of the eluent was taken at each time and filtered through a 0.45 μm PVDF syringe filter. During filtration, the first 2 mL of the filtrate was discarded, the subsequent 1 mL was used as the test solution, and the remaining 2 mL was returned to the elution vessel. After sample collection, 3 mL of fresh solution 1 was added to the vessel to maintain a constant total volume of the eluent. The collected test solution was diluted with methanol at a 1:1 (v / v) ratio, and the drug concentration was analyzed using an HPLC system.

[0216] Time (minutes) Emission rate (%) 5 92.74 10 96.73 15 98.76 30 100.71 45 101.23 60 101.60 90 101.79 120 101.29

[0217] As can be seen in Table 6, it was confirmed that the orally disintegrating tablet according to the present invention releases more than 90% of the drug within 5 minutes and more than 95% within 15 minutes under the first solution conditions, and through this, it was confirmed that the drug can be released immediately in the gastrointestinal environment to rapidly manifest its effect.

[0219] Experimental Example 2-3: Evaluation of in vitro taste masking

[0220] The taste masking degree of the oral disintegrating tablets of Examples 2-5 was analyzed using an electronic tongue system (α-Astree, Alpha MOS, France).

[0222] (1) Preparation of standard solution and test solution

[0223] Standard solution: Aqueous solutions with concentrations of 50, 100, 200, 400, and 800 μg / mL were prepared by dissolving the hydrochloride of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1H-pyrrole-3-yl)-N-methylmethaneamine in purified water (represented as “FPH 50 μg / mL”, “FPH 100 μg / mL”, “FPH 200 μg / mL”, “FPH 400 μg / mL”, and “FPH 800 μg / mL”, respectively), and 100 mL of the filtered solution was used after using a 0.45 μm PVDF syringe filter.

[0224] Control group: 40 mg of ion exchange resin (Amberlite™ IRP 88) was added to 200 mL of purified water and stirred for 1 minute, and 100 mL of the filtered solution was used.

[0225] Comparative group: 80 mg of the sample from Comparative Example 1-1 was added to 200 mL of purified water and stirred for 1 minute, and then 100 mL of the filtered liquid was used using a 0.45 μm PVDF syringe filter.

[0226] Test solution: The drug-ion exchange resin complex of Example 1-1 and the oral disintegrating tablet of Example 2-5 were each added to 200 mL of purified water and stirred for 1 minute, and then 100 mL of the filtered solution was used using a 0.45 μm PVDF syringe filter.

[0228] (2) Analysis and data processing

[0229] Each sample was analyzed six times for 2 minutes, and the collected electrical signal data was subjected to Principal Component Analysis (PCA) using dedicated software (Alpha soft V 16.0), and the results are shown in Fig. 5. In addition, the geometric distances of the standard solution, the comparison group, and the examples were measured based on the data points of the ion exchange resin itself, which served as the control group, and the results are shown in Table 7.

[0231] Sample Geometric distance based on ion exchange resin on the PCA map Examples 2-5 1613.14 Comparative Example 1-1 4504.34 FPH 50 μg / mL 7562.48 FPH 100 μg / mL 7435.77 FPH 200 μg / mL 7666.62 FPH 400 μg / mL 8150.06 FPH 800 μg / mL 8808.31

[0232] Referring to Fig. 5, it was confirmed that the oral disintegrating tablet according to the present invention is located on the left side of the PCA map, distinct from the standard solutions, and is located close to the ion exchange resin, which is a control group without a bitter taste.

[0233] In addition, as can be seen from Table 7, it was confirmed that the distance of the oral disintegrating tablet was closer to the physical mixture compared to the ion exchange resin without bitterness, and it was confirmed that the oral disintegrating tablet of the present invention effectively blocked the bitterness, unlike the physical mixture.

Claims

Claim 1 A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and a complex chemically bonded to a cation exchange resin, wherein the complex comprises 30 to 250 parts by weight of the cation exchange resin based on 100 parts by weight of the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] . Claim 2 A drug-ion exchange resin complex according to claim 1, wherein the cation exchange resin is a polymer containing carboxyl groups or a salt thereof. Claim 3 In claim 1, the cation exchange resin is a drug-ion exchange resin complex, wherein the cation exchange resin is a copolymer of methacrylic acid and divinylbenzene or a salt thereof. Claim 4 A drug-ion exchange resin complex according to claim 1, wherein the complex comprises 80 to 120 parts by weight of the cation exchange resin based on 100 parts by weight of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. Claim 5 In claim 1, the average particle size (D) of the composite is 50 ) is a drug-ion exchange resin complex having a particle size of 100 μm or less. Claim 6 An orally disintegrating tablet comprising a drug-ion exchange resin complex according to any one of claims 1 to 5. Claim 7 In claim 6, an orally disintegrating tablet comprising 10 to 50 weight% of the drug-ion exchange resin complex based on the total weight of the orally disintegrating tablet. Claim 8 In claim 6, the oral disintegrating tablet further comprises one or more additives selected from the group consisting of excipients, disintegrants, binders, sweeteners, flavorings, lubricants, and colorings. Claim 9 In claim 8, the above excipient is an orally disintegrating tablet in which mannitol and microcrystalline cellulose are mixed in a weight ratio of 5:1 to 1:

5. Claim 10 In claim 8, an orally disintegrating tablet comprising 55 to 85 weight% of the excipient based on the total weight of the orally disintegrating tablet. Claim 11 A method for manufacturing an orally disintegrating tablet, comprising: a step of preparing a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; a step of preparing a solution by dissolving the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof in a solvent; and a step of adding a cation exchange resin to the solution to induce an ion exchange reaction with the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof to form a complex, and a step of preparing a drug-ion exchange resin complex by reacting the cation exchange resin in an amount of 30 to 250 parts by weight per 100 parts by weight of the compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] . Claim 12 A method for manufacturing an orally disintegrating tablet according to claim 11, wherein the ion exchange reaction is carried out at 40°C to 60°C. Claim 13 A method for manufacturing an orally disintegrating tablet according to claim 11, wherein the above-mentioned complex is compressed by a direct compression method to produce an orally disintegrating tablet.

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