Orally disintegrating tablets comprising a benzimidazole derivative compound and a process for their preparation

Abstract

The present invention relates to an orally disintegrating tablet comprising a benzimidazole derivative compound and a process for preparing the same.

Description

TECHNICAL FIELD

[0001] The present application relates to an orally disintegrating tablet comprising a benzimidazole derivative compound and a preparation method thereof, and more particularly, to an orally disintegrating tablet comprising a wet granule comprising tegoprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a sweetening agent, and a preparation method thereof. BACKGROUND

[0002] Tegoprazan is a compound named (S)-4-(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (or 7-{[(4S)-5,7-difluoro-3,4-dihydro-2H-chroman-4-yl]oxy]}-N,N,2-trimethyl-1-benzimidazole-5-carboxamide), and is a potassium-competitive acid blocker (P-CAB) whose mechanism is similar to that of an acid pump antagonist (APA). It binds to potassium ions in terms of binding to H + / K + -ATPase (proton pump), is a component that excretes a component of gastric acid H + in the gastric parietal cell into the gastric cavity, thereby inhibiting the secretion of gastric acid.

[0003] Tegoprazan is used as a therapeutic agent for gastroesophageal reflux disease, and at least 70% of patients with gastroesophageal reflux disease are elderly people over 60 years of age who have difficulty swallowing. Many of those patients have poor swallowing ability, and thus have many difficulties in taking oral dosage forms such as tablets, capsules, etc.

[0004] Orally disintegrating tablets are convenient for those patients, but tegoprazan is a drug that exhibits a bitter taste even at a low concentration, and thus the development of tegoprazan in an orally disintegrating tablet is limited.

[0005] Accordingly, there is a need to develop an orally disintegrating tablet that can disintegrate in the oral cavity in a short time while exhibiting good sensory properties and having a masking type tegoprazan bitter taste.

[0006] [Related Art Documents]

[0007] [Patent Documents]

[0008] International Patent Publication No. WO 2007 / 072146 SUMMARY

[0009] TECHNICAL PROBLEM

[0010] The present application can provide an oral disintegrating tablet comprising a wet granule, the wet granule comprising tegoprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a sweetening agent.

[0011] The present application can provide a method for preparing an oral disintegrating tablet, the method comprising: (1) preparing a wet granule comprising tegoprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a sweetening agent; (2) preparing a mixture by adding one or more pharmaceutically acceptable additives to the wet granule; and (3) compressing the mixture into a tablet.

[0012] The present application can provide an oral disintegrating tablet prepared by the above preparation method.

[0013] Technical Solution

[0014] Terms not specifically defined in the present specification are understood to have the meanings commonly used in the art to which the present application pertains. In addition, the singular form includes the plural form, and vice versa, unless the context clearly dictates otherwise.

[0015] In the present specification, items are arbitrarily divided for the sake of description of the specification, and the content of any one item should not be construed as depending on the item.

[0016] Orally disintegrating tablet

[0017] The present application can provide an oral disintegrating tablet comprising a wet granule, the wet granule comprising: a compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a sweetening agent:

[0018] [Formula 1]

[0019]

[0020] The compound represented by the above Formula 1 is named (S)-4-(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, and is also referred to as tegoprazan.

[0021] In the present application, "pharmaceutically acceptable salt" can mean a salt formed with any inorganic acid, organic acid, or base, which neither causes serious irritation to a subject to which it is administered nor impairs the biological activity and physical properties of tgefazepam. The salt used herein can include a salt conventionally used in the art, for example, an acid addition salt formed with a pharmaceutically acceptable free acid. The pharmaceutically acceptable salt can be particularly selected from the group consisting of a pidolate, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, palmitate, pamoate, phosphate / dihydrogen phosphate / bisodium phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate, but is not limited thereto. Any salt can be used without limitation, as long as they can conventionally exhibit the pharmacological activity of the tgefazepam.

[0022] In the present application, "hydrate" can mean a substance in which tgefazepam or a pharmaceutically acceptable salt thereof is combined with water through non-covalent intermolecular forces, and can include a stoichiometric or non-stoichiometric amount of water.

[0023] In the present application, "solvate" can mean a substance in which tgefazepam or a pharmaceutically acceptable salt thereof is combined with a solvent other than water through non-covalent intermolecular forces, and can include a stoichiometric or non-stoichiometric amount of solvent.

[0024] In the present specification, tgefazepam can mean a compound represented by the above Formula 1, and a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture of all thereof.

[0025] In the present application, tgefazepam can exist in a crystalline or non-crystalline form.

[0026] The oral disintegrating tablet of the present application can include a wet granule, and the wet granule can include a compound represented by the above Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient.

[0027] The oral disintegrating tablet of the present application can be used for treating a disease mediated by acid pump antagonistic activity, since it is characterized in that the tablet comprises a compound represented by Formula 1 above, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0028] The disease mediated by acid pump antagonistic activity can be at least one selected from the group consisting of gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, purosis, nausea, esophagitis, dysphagia, sialorrhea, airway disorders, and asthma, and particularly can be gastroesophageal reflux disease (GERD), but is not limited thereto.

[0029] The "gastroesophageal reflux disease (GERD)" can refer to a case in which gastric contents reflux into the esophagus, causing symptoms that interfere with daily life or causing complications, and can be classified into erosive esophagitis (EE) and non-erosive reflux disease (NERD).

[0030] The oral disintegrating tablet of the present application can comprise a therapeutically effective amount of tegoprazan.

[0031] In the present application, the "therapeutically effective amount" can refer to an amount effective in preventing or treating a disease mediated by acid pump antagonistic activity.

[0032] The oral disintegrating tablet of the present application can comprise a wet granule, and the wet granule can comprise a sweetening agent.

[0033] In the present application, the wet granule can comprise a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a sweetening agent, in a weight ratio of 1:0.001 to 1:0.4.

[0034] The compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the sweetening agent can be specifically included in a weight ratio of 1:0.001 to 1:0.4, 1:0.005 to 1:0.35, and 1:0.01 to 1:0.3, more specifically 1:0.05 to 1:0.2, but are not limited thereto.

[0035] In this regard, in one specific embodiment of the present application, it is confirmed that if the oral disintegrating tablet of the present application comprises a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a sweetening agent in a weight ratio of 1:0.05 to 1:0.2, a smaller total amount of related substances is generated (Table 8).

[0036] In the present application, the sweetener can be one selected from the group consisting of sucralose, aspartame, saccharin, acesulfame potassium, stevioside, enzymatically modified steviol glycosides, sucrose, isomalt, maltitol, mannitol, sorbitol, steviol glycoside, erythritol, xylose, xylitol, lactitol, neotame, ribose, lyxose, polyol, advantam, tagatose, trehalose, glucose, maltose, dextrose, white sugar, fructose, honey, glycyrrhizin, monellin, rubusoside, mabinlin, corn syrup, lactose, oligosaccharide, and a mixture thereof, but is not limited thereto.

[0037] In this regard, in one specific embodiment of the present application, it was confirmed that the orally disintegrating tablet of the present application generates a smaller total amount of related substances, thereby exhibiting excellent stability regardless of the type of sweetener (Table 8).

[0038] In the present application, the content of the sweetener can be 0.01-10% by weight, specifically 0.01-10% by weight, 0.01-8% by weight, 0.07-6% by weight, 0.1-4% by weight, more specifically 0.1-3% by weight, and more specifically 0.7-2% by weight, based on the total weight of the tablet, but is not limited thereto.

[0039] The orally disintegrating tablet of the present application can further include a pharmaceutically acceptable additive.

[0040] The "pharmaceutically acceptable additive" can mean any additive that does not cause serious irritation to a subject to whom it is administered, nor impair the biological activity and physical properties of tegoprazan, and can specifically include an excipient, a disintegrant, a diluent, a flavoring agent, a sweetener, a lubricant, etc., but is not limited thereto.

[0041] The orally disintegrating tablet of the present application can further include a disintegrant as a pharmaceutically acceptable additive.

[0042] In the present application, the disintegrant can be any one selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, alginic acid, sodium alginate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, corn starch, pregelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium bicarbonate, and a mixture thereof, and specifically can be crospovidone, but is not limited thereto.

[0043] When crospovidone is used as the disintegrant, the size of the granule can be specifically 10-130 μm, more specifically 10-40 μm, but is not limited thereto.

[0044] In the present application, the content of the disintegrant can be 1-50% by weight, specifically 1-50% by weight, 1-40% by weight, 1-30% by weight, 1-20% by weight, and 1-10% by weight, more specifically 2-7% by weight, based on the total weight of the tablet, but is not limited thereto.

[0045] The orally disintegrating tablet of the present application can further comprise a diluent, a flavoring agent, a sweetening agent, a lubricant, or a mixture thereof as a pharmaceutically acceptable additive.

[0046] In the present application, the diluent can be any one selected from the group consisting of mannitol, lactose, starch, microcrystalline cellulose, ludipress (BASF), pearlitol flash (Roquette), calcium dihydrogen phosphate, dextrose, maltose, erythritol, sucrose, maltitol, trehalose, glucose, xylitol, F-melt (Fujichemical), sorbitol, pregelatinized starch, anhydrous calcium hydrogen phosphate, dicalcium phosphate, and a mixture thereof, but is not limited thereto.

[0047] In the present application, the content of the diluent can be 1-99% by weight, specifically 1-99% by weight, 5-97% by weight, 10-95% by weight, 15-92% by weight, more specifically 20-90% by weight, based on the total weight of the tablet, but is not limited thereto.

[0048] In the present application, the flavoring agent can be any one selected from the group consisting of a mint flavoring agent, a yogurt flavoring agent, a fruit flavoring agent, and a mixture thereof, and specifically can be a mint flavoring agent, but is not limited thereto. The fruit flavoring agent can specifically be an apple flavoring agent, a grape flavoring agent, a strawberry flavoring agent, or a lemon flavoring agent, but is not limited thereto.

[0049] In the present application, the content of the flavoring agent can be 0.01-10% by weight, specifically 0.05-8% by weight, 0.1-6% by weight, 0.2-4% by weight, more specifically 0.3-3% by weight, based on the total weight of the tablet, but is not limited thereto.

[0050] In addition to the sweetening agent contained in the wet granules, the orally disintegrating tablet of the present application can additionally contain a sweetening agent, and the sweetening agent that can be additionally contained can be any one selected from the group consisting of sucralose, aspartame, saccharin, acesulfame potassium, stevioside, enzymatically modified steviol glycosides, sucrose, isomalt, maltitol, mannitol, sorbitol, steviol glycoside, erythritol, xylose, xylitol, lactitol, neotame, ribose, tomatine, polyol, advantame, tagatose, trehalose, glucose, maltose, dextrose, white sugar, fructose, honey, glycyrrhizin, monellin, rebaudioside, curculin, lactose, oligosaccharide, and a mixture thereof, and specifically can be maltitol, sucralose, enzymatically modified steviol glycosides, or a mixture thereof, but is not limited thereto.

[0051] The sweetening agent contained in the wet granules and the sweetening agent additionally contained therein can be the same type or different types.

[0052] In the present application, the sweetening agent contained in the wet granules can be referred to as a first sweetening agent, and the sweetening agent additionally contained therein can be referred to as a second sweetening agent. In this case, "first", "second", and the like are used only to distinguish the plurality of components, and do not indicate the priority thereof.

[0053] The orally disintegrating tablet of the present application can contain the sweetening agent in an amount of 0.01-10% by weight, specifically 0.01-5% by weight, more specifically 0.1-3% by weight, based on the total weight of the tablet, without distinguishing the sweetening agent contained in the wet granules and the sweetening agent additionally contained therein, but is not limited thereto.

[0054] In the present application, the lubricant can be any one selected from the group consisting of stearic acid, a metal salt of stearic acid, talc, colloidal silicon dioxide, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glycerin fatty acid ester, glycerin dibehenate, and a mixture thereof, and specifically can be a metal salt of stearic acid, colloidal silicon dioxide, or a mixture thereof, but is not limited thereto. The metal salt of stearic acid can be more specifically calcium stearate or magnesium stearate, but is not limited thereto.

[0055] In the present application, the content of the lubricant can be 0.1-10% by weight, specifically 0.1-10% by weight, 0.2-8% by weight, 0.3-7% by weight, 0.4-6% by weight, more specifically 0.5-5% by weight, based on the total weight of the tablet, but is not limited thereto.

[0056] In the present application, the wet granules can be prepared by high-speed shear granulation or fluidized bed granulation, but are not limited thereto.

[0057] The wet granules can include wet granules prepared by collecting powder particles with a granulation fluid (a binder solution), and the granulation fluid can be used alone or in combination with a binder or an additive capable of providing a binding force, thereby imparting adhesion between the granules in a dry state.

[0058] In the present application, the wet granules can be prepared with a binder solution including any one selected from the group consisting of an alcohol, water, and a mixture thereof, and a sweetener.

[0059] In the wet granules prepared with the binder solution including a sweetener, the particles of tegoprazan and excipients can be physically tightly bound in the granules, i.e., can be attached and coated.

[0060] In the present application, the binder solution can further include a binder or an additive capable of providing a binding force.

[0061] The binder or the additive capable of providing a binding force can be any one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, polyethylene glycol, natural gums, synthetic gums, copovidone, ethyl cellulose, methacrylate copolymer, and a mixture thereof, and specifically can be hydroxypropyl methylcellulose, but is not limited thereto.

[0062] The binder or the additive capable of providing a binding force can be added as a solution or as a dry material mixed with primary powder particles.

[0063] In this regard, in one specific embodiment of the present application, the wet granules are prepared with a binder solution including a binder solution of a 58% (w / w) ethanol and a water solution of sucralose; a binder solution of a 50% (w / w) ethanol and a water solution of sucralose; a binder solution of a 50% (w / w) ethanol, hydroxypropyl methylcellulose, and a water solution of sucralose; a binder solution of a 50% (w / w) ethanol and a water solution of maltitol; or a binder solution of a 50% (w / w) ethanol and a water solution of aspartame.

[0064] The oral disintegrating tablet of the present application can rapidly disintegrate within 30 seconds.

[0065] In this regard, in one specific embodiment of the present application, it is confirmed that the oral disintegrating tablet of the present application disintegrates within 30 seconds in an in-vitro disintegration experiment, an in-vivo disintegration experiment, and a disintegration tester (Table 2).

[0066] The oral disintegrating tablet of the present application can exhibit excellent sensory properties with a masking bitter taste.

[0067] In this regard, in one embodiment of the present application, it was confirmed that the oral disintegrating tablet of the present application has little bitter taste and a soft disintegration feeling in the mouth, thereby effectively reducing the bitter taste and exhibiting excellent sensory properties (Table 3).

[0068] The oral disintegrating tablet of the present application can be disintegrated in the mouth in a short time and exhibit good sensory properties, such as a masking bitter taste, etc., thereby greatly improving the medication compliance of patients. Accordingly, the oral disintegrating tablet of the present application can effectively treat gastroesophageal reflux disease patients, particularly gastroesophageal reflux disease patients having difficulty in swallowing.

[0069] The oral disintegrating tablet of the present application can exhibit excellent dissolution rate.

[0070] In this regard, in one embodiment of the present application, it was confirmed that the oral disintegrating tablet of the present application exhibits excellent dissolution rate of tegoprazan at a level similar to that of the reference drug K-CAP tablet, without delayed release (Table 4, Figure 1 and Figure 2 ).

[0071] The oral disintegrating tablet of the present application can exhibit excellent stability.

[0072] In this regard, in one embodiment of the present application, it was confirmed that the oral disintegrating tablet of the present application generates a small total amount of related substances under stress and accelerated conditions, thereby exhibiting excellent stability (Table 6).

[0073] In this regard, in one embodiment of the present application, it was confirmed that the oral disintegrating tablet of the present application exhibits excellent stability in appearance under stress and accelerated conditions, without any appearance change due to moisture and heat on the surface of the tablet Figure 3 ).

[0074] Method for preparing an orally disintegrating tablet

[0075] The present application can provide a method of preparing an oral disintegrating tablet, the method comprising: (1) preparing a wet granule comprising: a compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a sweetening agent;

[0076] (2) preparing a mixture by adding one or more pharmaceutically acceptable additives to the wet granule; and

[0077] (3) compressing the mixture into a tablet:

[0078] [Formula 1]

[0079]

[0080] In the method for preparing the orally disintegrating tablet according to the present application, the contents described in the above orally disintegrating tablet item can be equally applied, unless there is a contradiction. Thus, the wet granules of the above orally disintegrating tablet, the components contained therein, the content of the respective components, the weight ratio of the respective components, the use, the effect, etc. can be directly applied to the method for preparing the orally disintegrating tablet, unless there is a contradiction.

[0081] In the present application, the sweetening agent can be any one selected from the group consisting of sucralose, aspartame, saccharin, acesulfame potassium, stevioside, enzymatically modified steviol glycosides, sucrose, isomalt, maltitol, mannitol, sorbitol, steviol glycoside, erythritol, xylose, xylitol, lactitol, neotame, ribose, lyxose, polyol, advantame, tagatose, trehalose, glucose, maltose, dextrose, white sugar, fructose, honey, glycyrrhizin, monellin, rubusoside, mabinlin, corn syrup, lactose, oligosaccharide, and a mixture thereof, and specifically can be sucralose, aspartame, or maltitol, but is not limited thereto.

[0082] In the present application, the preparation of the wet granules can be performed by wet granulation with a binder solution containing any one of an alcohol, water, and a mixture thereof, and a sweetening agent. The binder solution can specifically contain a mixture of an alcohol and water, more specifically an aqueous solution of ethanol, more specifically an aqueous solution of 58% (w / w) ethanol or an aqueous solution of 50% (w / w) ethanol, but is not limited thereto.

[0083] In the present application, the binder solution can further contain a binder or an additive capable of providing a binding force.

[0084] In the present application, the binder or the additive capable of providing a binding force can be any one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, amylopectin, polyethylene glycol, natural gum, synthetic gum, copovidone, ethyl cellulose, methacrylic acid ester copolymer, and a mixture thereof, and can be hydroxypropyl methylcellulose, but is not limited thereto.

[0085] In the present application, the wet granulation can be high-speed shear granulation or fluidized bed granulation, but is not limited thereto.

[0086] In the present application, the pharmaceutically acceptable additive can be a disintegrant, a diluent, a flavoring agent, a sweetening agent, a lubricant, or a mixture thereof, but is not limited thereto.

[0087] The disintegrant, the diluent, the flavoring agent, the sweetening agent, the lubricant, etc. are the same as those described in the above orally disintegrating tablet item.

[0088] In the present application, the sweetening agent can be used in the preparation of wet granules, and can also be additionally added as a pharmaceutically acceptable additive in the step of preparing a mixture.

[0089] The sweetening agent used in the preparation of wet granules and the sweetening agent additionally added in the preparation of a mixture can be the same type or different types.

[0090] In the present application, the sweetening agent used in the preparation of wet granules can be referred to as a first sweetening agent, and the sweetening agent used in the preparation of a mixture can be referred to as a second sweetening agent. In this case, "first", "second", and the like are used only to distinguish a plurality of components, and do not indicate priority thereof.

[0091] In the present application, the compression can be performed by using any tableting method commonly used in the field to which the present application pertains.

[0092] The present application can provide an oral disintegrating tablet prepared by the above-mentioned preparation method.

[0093] Pharmaceutical use of an orally disintegrating tablet

[0094] The present application can provide a method for preventing or treating a disease mediated by acid pump antagonistic activity, the method comprising administering an oral disintegrating tablet.

[0095] The present application can provide the use of an oral disintegrating tablet for preventing or treating a disease mediated by acid pump antagonistic activity.

[0096] The present application can provide the use of an oral disintegrating tablet for the preparation of a medicament for preventing or treating a disease mediated by acid pump antagonistic activity.

[0097] The disease mediated by acid pump antagonistic activity can be at least one selected from the group consisting of gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, purpura, nausea, esophagitis, dysphagia, sialorrhea, airway lesions, and asthma, and particularly can be gastroesophageal reflux disease (GERD), but is not limited thereto.

[0098] In the pharmaceutical use of the orally disintegrating tablet of the present application, the contents described in the orally disintegrating tablet item above can be applied equally, provided that there is no contradiction. Thus, the wet granules of the orally disintegrating tablet described above, the components contained therein, the content of the respective components, the weight ratio of the respective components, the use, the effects, etc. can be directly applied to the pharmaceutical use in the orally disintegrating tablet, provided that there is no contradiction.

[0099] Advantageous Effects

[0100] The orally disintegrating tablet of the present application can disintegrate in the oral cavity in a short time and exhibit excellent sensory properties, such as a masking bitter taste, etc., thereby greatly improving the patient's medication compliance.

[0101] In addition, compared to the existing bitter taste masking method (in the existing method, drug particles are coated with a polymer or a lipid component, or coated by using an enteric or gastric soluble matrix), the preparation method is simple and economical, and exhibits a rapid disintegration rate and excellent release rate (speed) without delaying the disintegration and release of the drug, and produces uniform tablets and small particles, thereby improving the patient's compliance with medication.

[0102] In addition, compared to the existing method for masking bitter taste by simply adding various types of high sweeteners and flavorings, the method does not show appearance changes (e.g., the appearance of dark brown spots) caused by moisture and heat on the surface of the tablet, thereby exhibiting excellent appearance stability and producing a small total amount of related substances, thereby exhibiting excellent stability. BRIEF DESCRIPTION OF DRAWINGS

[0103] Figure 1 FIG. illustrates the drug dissolution rate of the tablet prepared according to Example 1 and the K-CAP tablet at pH 1.2.

[0104] Figure 2 FIG. illustrates the drug dissolution rate of the tablet prepared according to Example 1 and the K-CAP tablet at pH 4.0.

[0105] Figure 3 FIG. illustrates the change in properties under pressure and acceleration conditions of the tablets prepared according to Example 1 and Comparative Example 1. DETAILED DESCRIPTION

[0106] Hereinafter, the present application will be described in greater detail by way of exemplary embodiments. However, these exemplary embodiments are provided only to illustrate the present application, and thus the scope of the present application is not limited thereto.

[0107] Example 1: Preparation of tegoprazan orally disintegrating tablet 1

[0108] Orally disintegrating tablets were prepared according to the materials and amounts described in Example 1 of Table 1 below. Specifically, a binder solution was prepared by adding the sweetener sucralose to a 58% (w / w) aqueous ethanol solution, followed by stirring for two hours or more until completely dissolved. The main ingredient, regorafenib, and the excipient mannitol 200 SD were sieved through a 25 mesh sieve, mixed in a high-speed shear mixer, and kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluid bed dryer and size-adjusted. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified steviol glycosides, peppermint flavor, and colloidal silicon dioxide were added as excipients, disintegrants, sweeteners, and flavors to the size-adjusted product, followed by mixing and lubrication by the addition of magnesium stearate. Thereafter, tableting was performed using a tablet press by a conventional tableting method. Each tablet was prepared to have a weight of 350 mg, and a hardness in the range of 5-8 kP.

[0109] Example 2: Preparation of tegoprazan orally disintegrating tablet 2

[0110] Orally disintegrating tablets were prepared according to the materials and amounts described in Example 2 of Table 1 below. Specifically, a binder solution was prepared by adding the binder hydroxypropyl methylcellulose (Pharmacoat 603) to a 50% (w / w) aqueous ethanol solution to completely dissolve, followed by the addition of the sweetener sucralose, followed by stirring for two hours or more until completely dissolved. The main ingredient, regorafenib, and the excipient mannitol 200 SD were sieved through a 25 mesh sieve, added to a fluid bed granulator (GPCG 1, manufactured by Glatt), granulated by spraying the binder solution, and then size-adjusted. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified steviol glycosides, peppermint flavor, and colloidal silicon dioxide were added as excipients, disintegrants, sweeteners, and flavors to the size-adjusted product, followed by mixing and lubrication by the addition of magnesium stearate. Thereafter, tableting was performed using a tablet press by a conventional tableting method. Each tablet was prepared to have a weight of 350.5 mg, and a hardness in the range of 5-8 kP.

[0111] Example 3: Preparation of tegoprazan orally disintegrating tablet 3

[0112] Orally disintegrating tablets were prepared according to the materials and amounts described in Example 3 of Table 1 below. Specifically, a binder solution was prepared by adding the sweetener maltitol to a 50% (w / w) aqueous ethanol solution, followed by stirring for two hours or more until completely dissolved. The main ingredient, regorafenib, and the excipient mannitol 200 SD were sieved through a 25 mesh sieve, mixed in a high-speed shear mixer, and kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluid bed dryer and size-adjusted. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified steviol glycosides, peppermint flavor, and colloidal silicon dioxide were added as excipients, disintegrants, sweeteners, and flavors to the size-adjusted product, followed by mixing and lubrication by the addition of magnesium stearate. Thereafter, tableting was performed using a tablet press by a conventional tableting method. Each tablet was prepared to have a weight of 350 mg, and a hardness in the range of 5-8 kP.

[0113] Example 4: Preparation of tegoprazan orally disintegrating tablet 4

[0114] Orally disintegrating tablets were prepared according to the materials and amounts described in Example 4 of Table 1 below. Specifically, a binder solution was prepared by adding the sweetener aspartame to a 50% (w / w) aqueous ethanol solution, followed by stirring for two hours or more until completely dissolved. The main ingredient, regorafenib, and the excipient mannitol 200 SD were sieved through a 25 mesh sieve, mixed in a high-speed shear mixer, and kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluid bed dryer and size-adjusted. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified steviol glycosides, peppermint flavor, and colloidal silicon dioxide were added as excipients, disintegrants, sweeteners, and flavors to the size-adjusted product, followed by mixing and lubrication by the addition of magnesium stearate. Thereafter, tableting was performed using a tablet press by a conventional tableting method. Each tablet was prepared to have a weight of 350 mg, and a hardness in the range of 5-8 kP.

[0115] Example 5: Preparation of tegoprazan orally disintegrating tablet 5

[0116] Oral disintegrating tablets were prepared according to the materials and amounts described in Example 5 of Table 1 below. Specifically, an adhesive solution was prepared by adding the sweetener sucralose to a 50% (w / w) aqueous ethanol solution, followed by stirring for two hours or more until completely dissolved. The main ingredients regorafenib and the excipient xylitol were sieved through a 25 mesh sieve, mixed in a high speed shear mixer, and kneaded and granulated with the addition of the adhesive solution. The granulated product was dried in a fluid bed dryer and size-adjusted. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified steviol glycosides, peppermint flavor, and colloidal silicon dioxide were added to the size-adjusted product as excipients, disintegrants, sweeteners, and flavors, followed by mixing and lubrication by the addition of magnesium stearate. Thereafter, tabletting was performed using a tablet press by a conventional tabletting method. Each tablet was prepared to have a weight of 350 mg, and a hardness in the range of 5-8 kP.

[0117] Comparative Example 1. Preparation of Regorafenib Oral Disintegrating Tablets 6

[0118] Oral disintegrating tablets were prepared according to the materials and amounts described in Comparative Example 1 of Table 1 below. Specifically, all the materials described in Comparative Example 1 of Table 1 were sieved through a 25 mesh sieve, mixed, and tabletted using a tablet press by a conventional tabletting method. Each tablet was prepared to have a weight of 350 mg, and a hardness in the range of 5-8 kP.

[0119] [Table 1]

[0120]

[0121] Experimental Example 1: Evaluation of disintegration time

[0122] Oral disintegrating tablets need to be administered while disintegrating in the oral cavity, and thus need to disintegrate quickly. Therefore, the disintegration time of tablets prepared according to Examples 1-5 and Comparative Example 1 was measured.

[0123] For the in-vitro disintegration experiment, a filter paper having a diameter of 90 mm (see WH1442090) was placed on a petri dish (100 x 10 mm), and then the filter paper in the petri dish was completely soaked with 10 mL of a 10% (w / w) aqueous cobalt (II) chloride hexahydrate solution, after which a tablet was placed thereon, so that the time taken until water reached the end face of the tablet due to capillary action was measured by visual inspection of the color change with the naked eye (three times).

[0124] For the in-vivo disintegration experiment, ten subjects were asked to take a tablet without water, in order to measure the time taken until the tablet was completely disintegrated by saliva in the oral cavity.

[0125] For the disintegration test in a disintegration tester, the disintegration test was measured according to the disintegration test method of the Korean Pharmacopoeia General Test Methods (n = 6).

[0126] The average of each test is shown in Table 2 below.

[0127]

Table 2

[0128] No. Hardness (kP) In vitro In vivo Disintegration tester Example 1 6 17 seconds 22 seconds 19 seconds Example 2 6 16 seconds 22 seconds 23 seconds Example 3 6 17 seconds 21 seconds 22 seconds Example 4 6 18 seconds 22 seconds 20 seconds Example 5 6 19 seconds 22 seconds 22 seconds Comparative Example 1 6 18 seconds 20 seconds 23 seconds

[0129] As a result, it was confirmed that the tablets prepared according to Examples 1 to 5 and Comparative Example 1 rapidly disintegrated within 30 seconds in the in-vitro disintegration test, in-vivo disintegration test, and disintegration test in a disintegration tester.

[0130] Experimental Example 2: Sensory evaluation

[0131] Ten subjects were asked to take the tablets prepared according to Examples 1 to 5 and Comparative Example 1 above without water, after which a sensory evaluation (irritation and bitterness) was performed. Each subject recorded the scores (0-5) for irritation and bitterness, and the scores obtained were averaged and shown in Table 3 below.

[0132]

Table 3

[0133]

[0134] As a result, it was confirmed that Comparative Example 1 prepared by a direct compression method with a sweetener in the form of an added powder had very strong bitterness and an unpleasant mouth feeling, while Examples 1 and 3 to 5 prepared by a high-speed shear granulation and Example 2 prepared by a fluidized bed granulation had very little bitterness and a feeling of smooth disintegration in the mouth because the binder solution containing a sweetener adhered to and coated the particles of tigecycline and excipients, thereby showing an effect of reducing bitterness and excellent sensory properties.

[0135] Experimental Example 3: Dissolution rate evaluation

[0136] The dissolution rate of the drug was compared between the tablet prepared according to Example 1 above and the 50 mg K-CAP tablet of HK Innoen Co., Ltd. according to the dissolution test of Chapter 3 of the pharmaceutical equivalence test standards. At the start of the test, samples of the dissolution test solution at pH 1.2 were collected at 0, 5, 10, 15, and 30 minutes, samples of the dissolution test solution at pH 4.0 were collected at 0, 5, 10, 15, 30, 45, 60, 90, and 120 minutes, and liquid chromatography analysis was performed under the following conditions, after which the dissolution rate of tigecycline was calculated and shown in Table 4 and Figure 1 and 2 below.

[0137] < Dissolution conditions >

[0138] - Number of rotations: 50 rpm

[0139] - Amount of test solution: 900 mL

[0140] - Temperature of test solution: 37 ± 0.5°C

[0141] - Test solution: Solutions at pH 1.2 and pH 4.0 of the Korean Pharmacopoeia

[0142] < Liquid chromatography analysis conditions >

[0143] - Column: Column filled with octadecylsilylated silica gel for liquid chromatography analysis having a particle size of 5 μm in a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm

[0144] - Column temperature: Constant temperature of about 30°C

[0145] - Injection amount: 10 μL

[0146] - Mobile phase: 0.01 mol / L ammonium acetate buffer: ACN = 11:9

[0147] - Flow rate: 1.0 mL / min

[0148] - Detector: Ultraviolet absorbance photometer (measurement wavelength of 262 nm)

[0149]

Table 4

[0150]

[0151] As a result, it was confirmed that the tablet prepared according to Example 1 exhibited excellent tegoprazan dissolution rate at a level similar to that of the control drug K-CAP tablet without any delayed release.

[0152] Experimental Example 4: Stability evaluation

[0153] In order to evaluate the stability of Example 1 and Comparative Example 1 under stress and accelerated conditions, stability tests were performed under stress conditions (60°C, 80% RH) and accelerated conditions (40°C, 75% RH) in HDPE bottles and PTP (aluminum) packaging materials, and the total amount of related substances and changes in appearance thereof are shown in Tables 6 and 7 below, respectively. Figure 3

[0154] < Liquid chromatography analysis conditions >

[0155] - Column: Column filled with octadecylsilylated silica gel for liquid chromatography analysis having a particle size of 2.7 μm in a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm​

[0156] - Column temperature: constant temperature of about 30°C

[0157] - Injection volume: 10 μL

[0158] - Mobile phase A: 0.01 mol / L ammonium acetate buffer: ACN = 19:1

[0159] Mobile phase B: ACN

[0160] - Flow rate: 0.8 mL / min

[0161] - Detector: UV absorbance photometer (measurement wavelength of 220 nm)

[0162] Table 5

[0163]

[0164] Table 6

[0165]

[0166] As a result, it was confirmed that the tablet prepared according to Example 1 produced less total amount of related substances under stress and accelerated conditions compared to the tablet prepared according to Comparative Example 1 (Table 6), and the tablet of Comparative Example 1 produced blackish brown spots on the surface of the tablet under stress and accelerated conditions, whereas the tablet prepared according to Example 1 did not show appearance change under stress and accelerated conditions Figure 3 ), thereby exhibiting excellent stability.

[0167] Experimental Example 5: Stability evaluation according to sweetener type and weight ratio

[0168] In order to evaluate the stability under stress conditions according to the type of sweetening agent contained in the granules and the weight ratio of tigecycline and sweetening agent in the granules, oral disintegrating tablets were prepared according to the materials and contents described in the following Table 7 (Examples 6 to 10 and Comparative Example 2 were prepared by the same method as in Example 1), and thus stability tests were performed under stress conditions (60°C, 80% RH).

[0169] The total amount of related substances is shown in the following Table 8.

[0170] Table 7

[0171]

[0172] Table 8

[0173] Classification Example 6 Example 7 Example 8 Comparative Example 2 Example 9 Example 10 Tegoprazan: sucralose 1:0.05 1:0.1 1:0.2 1:0.5 - - Tegoprazan: aspartame - - - - 1:0.2 - Tegoprazan: maltitol - - - - - 1:0.2 Initial 0.08 0.08 0.08 0.08 0.10 0.10 Stress 2 weeks 0.08 0.08 0.08 0.99 0.11 0.10 Stress 4 weeks 0.08 0.08 0.08 1.91 0.11 0.10

[0174] As a result, it was confirmed that the tablets of Examples 6 to 10 in which the weight ratio of tegoprazan to sweetener was 1:0.05 to 1:0.2 produced a smaller total amount of the relevant substances than the tablets of Comparative Example 2 in which the weight ratio of tegoprazan to sweetener was 1:0.5, thereby exhibiting excellent stability.

[0175] Meanwhile, it was confirmed that the tablets of Example 8 having sucralose, the tablets of Example 9 having aspartame, and the tablets of Example 10 having maltitol all produced a smaller total amount of the relevant substances depending on the type of sweetener, thereby exhibiting excellent stability regardless of the type of sweetener.

[0176] While specific portions of the application have been described above, it is evident that the detailed description is illustrative only and not restrictive of the present application. Thus, it will be understood that notwithstanding the numerical embodiments falling within the scope of the application, equivalents there are to be included. Accordingly, the scope of the present application is defined only by the appended claims and equivalents thereof.

Claims

1. An orally disintegrating tablet comprising wet granules, said wet granules comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a mixture thereof; and a sweetener. The sweetener described herein is selected from one or more of the following groups: sucralose, aspartame, saccharin, acesulfame potassium, steviol glycosides, enzyme-modified steviol glycosides, sucrose, isomaltitol, maltitol, mannitol, sorbitol, erythritol, xylose, xylitol, lactitol, neotame, ribose, adventitol, tagatose, trehalose, glucose, maltose, white sugar, fructose, glycyrrhizin, raspberry glycoside, corn syrup, and lactose. [Formula 1] ， The wet granules contain, in a weight ratio of 1:0.05 to 1:0.2, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a mixture thereof, and the sweetener. The wet particles are prepared using a binder solution comprising one or more of the group consisting of alcohols and water, and the sweetener.

2. The oral disintegrating tablet according to claim 1, wherein the sweetener content is 0.01-10% by weight based on the total weight of the tablet.

3. The oral disintegrating tablet according to claim 1, wherein the oral disintegrating tablet further comprises a disintegrant.

4. The oral disintegrating tablet according to claim 3, wherein the disintegrant is one or more selected from the group consisting of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium starch glycolate, alginate, sodium alginate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, corn starch, pregelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose and sodium bicarbonate.

5. The oral disintegrating tablet according to claim 3, wherein the content of the disintegrant is 1-50% by weight based on the total weight of the tablet.

6. The oral disintegrating tablet of claim 1, wherein the oral disintegrating tablet further comprises a diluent, a flavoring agent, a lubricant, or any combination thereof.

7. The oral disintegrating tablet according to claim 6, wherein the diluent is selected from one or more of the group consisting of mannitol, lactose, starch, microcrystalline cellulose, ludipress, pearlitol flash, calcium dihydrogen phosphate, dextrose, maltose, erythritol, sucrose, maltitol, trehalose, glucose, xylitol, F-melt, sorbitol, pregelatinized starch, anhydrous calcium hydrogen phosphate, and dicalcium phosphate.

8. The oral disintegrating tablet of claim 6, wherein the content of the diluent is 1-99% by weight based on the total weight of the tablet.

9. The oral disintegrating tablet of claim 6, wherein the flavoring agent is one or more selected from other sweeteners, mint flavoring agents, yogurt flavoring agents, and fruit flavoring agents.

10. The oral disintegrating tablet of claim 6, wherein the flavoring agent content is 0.01-10% by weight based on the total weight of the tablet.

11. The oral disintegrating tablet according to claim 6, wherein the lubricant is one or more selected from the group consisting of stearic acid, metal stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glycerol fatty acid ester and disorbate glyceride.

12. The oral disintegrating tablet of claim 6, wherein the lubricant content is 0.1-10% by weight based on the total weight of the tablet.

13. The oral disintegrating tablet of claim 1, wherein the binder solution further comprises a binder or additive capable of providing binding strength.

14. The oral disintegrating tablet of claim 13, wherein the binder or additive capable of providing binding force is one or more selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, amylopectin, polyethylene glycol, natural gums, synthetic gums, copovidone, ethyl cellulose, and methacrylate copolymers.

15. The oral disintegrating tablet according to claim 1, wherein the wet granules are prepared by high-speed shear granulation or fluidized bed granulation.

16. The oral disintegrating tablet of claim 1, wherein the oral disintegrating tablet disintegrates within 30 seconds.

17. The oral disintegrating tablet of claim 1, wherein the oral disintegrating tablet has a masked bitter taste.

18. The oral disintegrating tablet of claim 1, wherein the oral disintegrating tablet is used for the prevention or treatment of diseases mediated by acid pump antagonistic activity.

19. The oral disintegrating tablet of claim 18, wherein the disease mediated by acid pump antagonistic activity is at least one selected from the group consisting of gastroesophageal reflux disease (GERD), peptic ulcer, gastritis, Helicobacter pylori infection, dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), nausea, esophagitis, dysphagia, and drooling.

20. The oral disintegrating tablet of claim 19, wherein the peptic ulcer is selected from gastric ulcer, duodenal ulcer, or NSAID-induced ulcer.

21. A method for preparing orally disintegrating tablets, comprising: (1) Preparing wet granules, said wet granules comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a mixture thereof, and a sweetener; (2) A mixture is prepared by adding one or more pharmaceutically acceptable additives to the wet granules; and (3) Compress the mixture into tablets. The sweetener described herein is selected from one or more of the following groups: sucralose, aspartame, saccharin, acesulfame potassium, steviol glycosides, enzyme-modified steviol glycosides, sucrose, isomaltitol, maltitol, mannitol, sorbitol, erythritol, xylose, xylitol, lactitol, neotame, ribose, adventitol, tagatose, trehalose, glucose, maltose, white sugar, fructose, glycyrrhizin, raspberry glycoside, corn syrup, and lactose. [Formula 1] ， The wet granules contain, in a weight ratio of 1:0.05 to 1:0.2, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a mixture thereof, and the sweetener. The wet particles are prepared using a binder solution comprising one or more of the group consisting of alcohols and water, and the sweetener.

22. The method of claim 21, wherein the adhesive solution further comprises an adhesive or additive capable of providing bonding strength.

23. The method of claim 22, wherein the adhesive or additive capable of providing bonding strength is one or more selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, amylopectin, polyethylene glycol, natural gums, synthetic gums, copovidone, ethyl cellulose, and methacrylate copolymers.

24. The method of claim 21, wherein the wet particles are prepared by high-speed shear granulation or fluidized bed granulation.

25. The method of claim 21, wherein the pharmaceutically acceptable additive is a disintegrant, a diluent, a flavoring agent, a lubricant, or any combination thereof.

26. The method of claim 21, wherein the pharmaceutically acceptable additive is a disintegrant, a diluent, an additional sweetener, a lubricant, or any combination thereof.

27. An oral disintegrating tablet, said oral disintegrating tablet being prepared by the method according to any one of claims 21-26.

28. Use of the oral disintegrating tablets according to any one of claims 1-20 in the preparation of a medicament for the prevention or treatment of diseases mediated by acid pump antagonistic activity, wherein the diseases mediated by acid pump antagonistic activity are at least one selected from the group consisting of gastroesophageal reflux disease (GERD), peptic ulcer, gastritis, Helicobacter pylori infection, dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), nausea, esophagitis, dysphagia, and drooling.

29. The use according to claim 28, wherein the peptic ulcer is selected from gastric ulcers, duodenal ulcers, or NSAID-induced ulcers.

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