Pharmaceutical compositions containing benzimidazole derivative compounds

Abstract

The present disclosure relates to a pharmaceutical composition containing a benzimidazole derivative compound. Specifically, the present disclosure relates to a formulation that can sustainably maintain the blood concentration of the benzimidazole derivative compound.

Description

[Technical field]

[0001] The present disclosure relates to a pharmaceutical composition containing a benzimidazole derivative compound. Specifically, the present disclosure relates to a preparation capable of sustaining the blood concentration of the benzimidazole derivative compound. [Background technology]

[0002] Tegoprazan is the world's first potassium-competitive acid blocker (P-CAB), which has a mechanism similar to that of acid pump antagonists (APAs) and inhibits gastric acid secretion by competitively binding with potassium ions to the enzyme H+ / K+-ATPase (proton pump), which secretes H+ ions, a component of gastric acid, from gastric parietal cells into the gastric lumen. Tegoprazan is not a prodrug like proton pump inhibitors (PPIs), so it does not require an activation process and can act not only on active proton pumps but also on inactive proton pumps. Therefore, tegoprazan has the advantage of being rapidly effective, reaching its maximum effect within one hour.

[0003] On the other hand, in general, in order for a drug to exert the expected effect, it is necessary to maintain the blood concentration of the drug at a certain level or higher. In order to maintain the blood concentration of the drug, the prescribed drug must be taken repeatedly according to a certain schedule. In this case, frequent taking of the drug reduces the patient's compliance with taking the drug, and as a result, the expected therapeutic effect is often not obtained. Thus, in diseases that require long-term drug administration or diseases that require the blood concentration of the drug to be maintained at a certain level or higher during times when the patient cannot take the drug, the frequency of administration and the method of administration are also important factors in order to enhance the therapeutic effect of the drug.

[0004] Therefore, there is a demand for the development of a preparation that can maintain a therapeutically effective blood concentration of a drug while regulating the release of the drug and without causing problems with the drug absorption rate. DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0005] It is an object of the present disclosure to provide a modified-release pharmaceutical composition comprising, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a release modifying agent.

[0006] An object of the present disclosure is to provide a modified release pharmaceutical composition comprising a core containing tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient; and a release modifier-containing layer formed on the core.

[0007] It is an object of the present disclosure to provide a capsule filled with a modified release pharmaceutical composition.

[0008] It is an object of the present disclosure to provide a tablet comprising a modified release pharmaceutical composition.

[0009] It is an object of the present disclosure to provide a formulation comprising a first pharmaceutical composition of modified release type containing tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient; and a second pharmaceutical composition of immediate release type containing tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient. [Means for solving the problem]

[0010] Terms not specifically defined herein are understood to have the same meaning as commonly used in the technical field to which this disclosure belongs. Furthermore, a singular expression includes a plural expression, and a plural expression also includes a singular expression unless otherwise specified in the context.

[0011] In this specification, terms first, second, etc. are used for classification purposes only and are not intended to specify an order or position.

[0012] Sections are divided arbitrarily herein for convenience of description only, and the contents of any one section should not be construed as being subordinate to that section.

[0013] As used herein, a multi-layer tablet may be a tablet having one or more layers disposed on a core surrounding the core, the one or more layers may be a coating layer and / or a matrix layer. For example, a multi-layer tablet may be a tab-in-tab as illustrated in FIG. 1A.

[0014] In addition, in the present specification, the multi-layer tablet may be in the form in which one or more layers are continuously laminated, as illustrated in Figure 1B. For example, the multi-layer tablet may be a two-layer tablet, a three-layer tablet, etc.

[0015] As used herein, tegoprazan is a compound represented by the following formula I, and has the chemical name (S)-4- ( (5,7-difluorochroman-4-yl ) Oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide Do Yes. [Formula I] JPEG0007652787000001.jpg5164

[0016] In this specification, the term "tegoprazan" may refer to tegoprazan, its optical isomer, its pharma- ceutically acceptable salt, its hydrate or solvate, or a mixture thereof. In addition, in this specification, the term "tegoprazan" may be used interchangeably with the term "active ingredient."

[0017] In the present invention, a "pharmaceutical acceptable salt" may be an acid addition salt or a base addition salt. Acid addition salts can be prepared from acids which form non-toxic salts, examples of which include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, hexafluorophosphate, hybenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / chloride, and the like. Examples of base addition salts include iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / phosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Examples of base addition salts include alkali metal salts such as lithium salt, sodium salt, and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; and organic base salts such as triethylamine salt, diisopropylamine salt, or cyclohexylamine salt. The base addition salt may be specifically an alkali metal salt, more specifically a sodium salt.

[0018] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Where appropriate, pharma- ceutically acceptable salts of compounds of formula I can be readily prepared by mixing a solution of the compound of formula I with the desired acid or base. The salt may precipitate from solution and be recovered by filtration or the salt may be recovered by evaporating the solvent. The degree of ionization in the salt may vary from fully ionized to almost non-ionized.

[0019] As used herein, the term "immediate release (IR)" means that the active ingredient is released immediately or shortly after administration.

[0020] In the present specification, the term "controlled release (CR) or modified-release (MR)" means to control the release of a drug so that the active ingredient is released at a specific location in the digestive tract or after a certain time after taking the drug, or so that the active ingredient is released continuously in the digestive tract for a long period of time, or so that the active ingredient is released continuously over a long period of time while being released at a specific location in the digestive tract or after a certain time after taking the drug. That is, in the present specification, the term "controlled release" or "controlled release" may include delayed release and / or extended release or sustained release. Specifically, "controlled release" or "controlled release" may be delayed release in which the drug is released after a certain time after taking the drug; or sustained release in which the drug is released slowly over a certain time or more after taking the drug; or delayed release and sustained release in which the drug is released after a certain time after taking the drug and slowly released over a certain time. For example, delayed release means that the drug begins to be released in an environment other than gastric fluid after ingestion, and sustained release may mean that the drug is continuously released in the region from the gastric environment to the intestinal environment after ingestion, or that the drug begins to be released in an environment other than gastric fluid and then is continuously released. As used herein, the terms "modified release" and "controlled release" may be interchangeable.

[0021] Modified release pharmaceutical compositions The present disclosure provides a modified release pharmaceutical composition comprising, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a release modifier.

[0022] In the examples of the present disclosure, the release modifying agent may include at least one selected from the group consisting of a release sustaining agent and an enteric agent.

[0023] In one embodiment, the modified release pharmaceutical composition of the present disclosure may include a release sustaining agent.

[0024] In another embodiment, the modified release pharmaceutical compositions of the present disclosure may include an enteric agent.

[0025] In another embodiment, the modified release pharmaceutical compositions of the present disclosure may include a release sustaining agent and an enteric agent.

[0026] The pharmaceutical composition of the present disclosure is a modified release pharmaceutical composition of tegoprazan. For example, tegoprazan may be delayed, sustained, or delayed and sustained from the pharmaceutical composition. Specifically, the pharmaceutical composition of the present disclosure may release tegoprazan after passing through the gastric environment and then reaching the intestine (e.g., duodenum, small intestine, etc.) (i.e., delayed release), or may release tegoprazan continuously from the gastric environment over a long period of time, or may start to release tegoprazan after passing through the gastric environment and then reaching the intestine (delayed release), and then continuously release tegoprazan over a long period of time.

[0027] In this way, the modified release pharmaceutical composition of the present disclosure can maintain a high blood concentration of the active ingredient tegoprazan for a certain period of time after administration, thereby significantly improving the patient's compliance with medication. Specifically, the composition of the present disclosure can release tegoprazan after passing through the gastric fluid environment, can release it continuously in the region from the gastric fluid to the intestinal environment, or can start releasing it after passing through the gastric fluid environment and release it continuously. Therefore, the composition of the present disclosure can exert its medicinal effect even after a certain period of time has passed after administration, thereby significantly improving the patient's compliance with medication. In addition, the composition of the present disclosure can exert excellent medicinal effect for a long period of time even at a low dose, thereby minimizing side effects and maximizing drug effect.

[0028] This modified release pharmaceutical composition exhibits excellent solubility even in an environment with a higher pH than the gastric fluid environment, and as a result, can exhibit excellent solubility even in an intestinal fluid environment, for example, in the duodenum, small intestine, etc. Furthermore, even when tegoprazan is released delayed or released continuously after the delayed release, the drug release can be adjusted to achieve a therapeutic blood concentration of tegoprazan without decreasing the dissolution rate.

[0029] In examples of the present disclosure, the modified release pharmaceutical composition of the present disclosure can include particles comprising tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, as an active ingredient.

[0030] In the present disclosure, the term "particle" may be used interchangeably with the term "tegoprazan-containing particle."

[0031] In the examples of the present disclosure, the particles may be pellets, tablets, or granules.

[0032] When the particle is a pellet, the pellet may comprise: an inert particle; and an active ingredient layer formed on the inert particle, the active ingredient layer comprising tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, as an active ingredient.

[0033] The modified release pharmaceutical composition of the present invention may contain a release modifier inside and / or outside the active ingredient layer. For example, the modified release pharmaceutical composition may contain a release modifier inside the active ingredient layer, may contain a release modifier layer formed on the active ingredient layer, or may contain both a release modifier in the active ingredient layer and a release modifier layer formed on the active ingredient layer.

[0034] The release modifier may be a release modifier and / or an enteric coating. For example, when the composition contains a release modifier both inside and outside the active ingredient layer, the release modifier contained in the active ingredient layer and the release modifier contained outside the active ingredient layer may be the same or different. Specifically, the active ingredient layer may contain a release modifier, an enteric coating, or both, the outside of the active ingredient layer may contain a release modifier, an enteric coating, or both, and the agents contained inside and outside the active ingredient layer may be independent of each other.

[0035] In an example of the present disclosure, the release modifier may be included inside the active ingredient layer. In another example of the present disclosure, the release sustaining agent may be included outside the active ingredient layer. In this case, the release sustaining agent may be included in a release sustaining agent-containing layer formed on the active ingredient layer. In yet another example of the present disclosure, the release sustaining agent may be included inside and outside the active ingredient layer. In another example of the present disclosure, the release sustaining agent may be included inside the active ingredient layer, and the enteric agent may be included outside the active ingredient layer. In yet another example of the present disclosure, the release sustaining agent may be included inside the active ingredient layer, and the release sustaining agent and the enteric agent may be included outside the active ingredient layer, in which case the release sustaining agent layer formed on the active ingredient layer and the enteric agent layer formed on the release sustaining agent layer may be included outside the active ingredient layer.

[0036] In one embodiment, the pellet may comprise inert particles and an active ingredient layer formed on the inert particles, the active ingredient layer may comprise a first release modifier. In another embodiment, the pellet may comprise a second release modifier layer comprising a second release modifier formed on the active ingredient layer comprising the first release modifier. Or, in yet another embodiment, the pellet may comprise inert particles; an active ingredient layer formed on the inert particles; and a first release modifier layer formed on the active ingredient layer.

[0037] In the above embodiment, the first release modifier may be a sustained release agent and the second release modifier may be a sustained release agent or an enteric agent. In one example, the second release modifier may be an enteric agent. In another example, the second release modifier may be a release modifier, in which case the pellet may include a third release modifier layer formed on the second release modifier layer, and the third release modifier layer may include an enteric agent.

[0038] The active ingredient layer and the release regulator layer may each independently contain a pharma- ceutically acceptable additive. Examples of pharma-ceutically acceptable additives include, but are not limited to, anti-adhesive agents, plasticizers, surfactants, disintegrants, excipients, etc. The content and type of pharma-ceutically acceptable additives can be appropriately selected by those skilled in the art.

[0039] The term "inert particles" as used herein may refer to pharmaceutical additives that are materials of regular or irregular shape that do not contain pharmacologically active materials.In the present disclosure, inert particles may be used alone or mixed with active ingredients and / or other pharmaceutically acceptable additives, and can function as seeds for coating layers formed in the pharmaceutical composition of the present disclosure.

[0040] In embodiments of the present disclosure, the inert particles include any one or more selected from pharma- ceutically acceptable inert substances, such as, for example, sucrose, lactose, starch, mannitol, sucrose, dextrin, or microcrystalline cellulose, and preferably include, but are not limited to, sucrose.

[0041] In an embodiment of the present disclosure, the pharmaceutical composition may further comprise an organic acid. According to one embodiment, the inert particles may comprise an organic acid or may be a material prepared solely with an organic acid. According to another embodiment, a layer containing an organic acid may be separately disposed within the core or may be disposed outside the core.

[0042] The organic acid can play a role of improving the solubility of the active ingredient. When the pharmaceutical composition contains an organic acid, the organic acid can play a role of improving the solubility of tegoprazan and increasing its in vivo absorption rate. For example, the enteric coating-containing layer in the pharmaceutical composition of the present disclosure completely or partially dissolves under weakly alkaline conditions, thereby dissolving or suspending tegoprazan, and the organic acid contained in the pharmaceutical composition dissolves, thereby improving the solubility of the suspended tegoprazan, thereby improving its solubility and in vivo absorption rate.

[0043] The organic acid may be, for example, any one or more selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, and aspartic acid. Specifically, the organic acid may be any one or more selected from tartaric acid, fumaric acid, succinic acid, and citric acid. More specifically, the organic acid may be tartaric acid, but is not limited thereto. In addition, in the present disclosure, the organic acid may include a hydrate or salt form.

[0044] In embodiments of the present disclosure, the weight ratio of the inert particles to the active ingredient contained in the core may be, but is not limited to, 5:1 to 1:5, specifically 3:1 to 1:3, more specifically 1:5 to 1:1.5, and even more specifically 1:1.

[0045] In the examples of the present disclosure, the active ingredient layer may further include pharma- ceutically acceptable additives, for example, the active ingredient layer may include povidone, polyethylene glycol, talc, polysorbate, or mixtures thereof.

[0046] In the present disclosure, the inert particles can be prepared by conventional preparation methods such as direct compression, compression of anhydrous, wet or sintered granules, extrusion followed by rounding, wet or dry granulation, or direct pelletization. In particular, when the inert particles are pellets, they can be prepared by, but not limited to, the pan method on a pelletizing plate or extrusion-rounding.

[0047] When the particles are granules, the granules may be prepared from a mixture of an active ingredient and a pharma- ceutically acceptable additive. In this case, the granules may be wet granules or dry granules.

[0048] In the examples of the present disclosure, the granule may contain a release modifier inside and outside the granule, and the release modifier may be a release sustaining agent and / or an enteric coating. When the release modifier is contained inside the granule, the granule may be formed from a mixture of the active ingredient and the release modifier. When the release modifier is contained outside the granule, the release modifier may be contained outside (on) the granule containing the active ingredient; or may be contained in the granule containing the active ingredient and the release modifier. Also, when the granule contains a release modifier both inside and outside the granule, the release modifier contained inside the granule and the release modifier contained outside the granule may be the same or different from each other. Specifically, the inside of the granule may contain a release sustaining agent, an enteric coating, or both, and the outside of the granule may contain a release sustaining agent, an enteric coating, or both, and in this case, the release modifiers contained inside and outside the granule may be independent of each other.

[0049] In examples of the present disclosure, the release sustaining agent may be included inside the granule. In other examples of the present disclosure, the release sustaining agent may be included outside the granule. In yet other examples of the present disclosure, the release sustaining agent may be included inside and outside the granule. In other examples of the present disclosure, the release sustaining agent may be included inside the granule and the enteric agent may be included outside the granule. In yet other examples of the present disclosure, the release sustaining agent and the enteric agent may be included outside the granule with or without the release sustaining agent therein, in which case the granule may include a release sustaining agent layer formed on the exterior of the granule and an enteric agent layer formed on the release sustaining agent layer.

[0050] When the particles are tablets, the tablets may be in the form of tablets produced by compressing granules, pellets or a mixture thereof containing the active ingredient with pharma- ceutically acceptable excipients, in which case the granules may be wet or dry granules, and the pellets may include a coating layer containing the active ingredient within the inert particles.

[0051] In addition, the tablets may contain release modifiers internal and / or external (on the tablet) and the description of the release modifiers may be the same as those described above for the internal and / or external release modifiers of the pellets and granules, respectively, unless inconsistent.

[0052] In an example of the present disclosure, the tablet may include a release sustaining agent inside the tablet. In another example of the present disclosure, the release sustaining agent may be included on the exterior (on the tablet) of the tablet. In yet another example of the present disclosure, the release sustaining agent may be included inside and on the exterior of the tablet. In another example of the present disclosure, the release sustaining agent may be included inside the tablet and the enteric agent may be included on the exterior of the tablet. In yet another example of the present disclosure, the release sustaining agent and the enteric agent may be included on the exterior of the tablet with or without the release sustaining agent, in which case the tablet may include a release sustaining agent layer formed on the tablet and an enteric agent layer formed on the release sustaining agent layer.

[0053] In the present disclosure, the active ingredient tegoprazan may exist in crystalline or amorphous form.

[0054] In an example of the present disclosure, the present disclosure provides a modified release pharmaceutical composition comprising: a core comprising, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a release modifier-containing layer formed on the core.

[0055] The release modifier-containing layer may include a release sustaining agent-containing layer and / or an enteric agent-containing layer. In this disclosure, the terms "release modifier-containing layer", "release sustaining agent-containing layer", and "enteric agent-containing layer" can be used interchangeably with the terms "release modifier layer", "release sustaining agent layer", and "enteric agent layer", respectively.

[0056] As used herein, the term "core" refers to the center or part that constitutes the core of a pharmaceutical composition. The core may be completely coated with a coating layer formed later and located at the center of the pharmaceutical composition, but a part of the core may be uncoated as long as its function is not significantly different from that of a completely coated core. The core may also be positioned so as to be biased toward one side of the pharmaceutical composition.

[0057] The core may comprise a particle comprising, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the core may be a particle.

[0058] The particles are substantially the same as those described above for particles containing tegoprazan, unless otherwise stated.

[0059] Specifically, in the examples of the present disclosure, the core may include inert particles; and an active ingredient layer containing an active ingredient formed on the inert particles.

[0060] The inert particles and active ingredient layer are substantially the same as described above unless otherwise stated.

[0061] According to an embodiment of the present disclosure, the core may be a mixture of an active ingredient and a pharma- ceutically acceptable additive. In this case, the active ingredient and the pharma- ceutically acceptable additive may be present throughout the core, for example, mixed in a single matrix form. According to one embodiment, the core may be a granule prepared from a mixture of the active ingredient and the pharma- ceutical acceptable additive. In this case, the granule may be a wet granule or a dry granule. According to another example, the core may be in the form of a core tablet prepared by compressing a granule, pellet, or a mixture thereof containing the active ingredient and the pharma- ceutical acceptable additive. In this case, the granule may be a wet granule or a dry granule, and the pellet may include an active ingredient-containing coating layer on an inert particle.

[0062] Examples of pharma- ceutically acceptable additives include, but are not limited to, anti-adhesion agents, plasticizers, surfactants, disintegrants, excipients, and the like.

[0063] The core may include a release modifying agent, specifically the core may include a release sustaining agent and / or an enteric agent, more specifically the core may include a release sustaining agent.

[0064] The modified release pharmaceutical compositions of the present disclosure may also include a release sustaining agent.

[0065] In the present disclosure, the release sustaining agent may be a substance capable of sustaining the release of a drug for a predetermined period of time by slowing down the release rate of the drug from the pharmaceutical composition of the present disclosure. In the present disclosure, the release sustaining agent may include, but is not limited to, a water-insoluble and / or poorly water-soluble material having sufficient properties to enable the sustained release of the active ingredient, such as a sufficient viscosity to enable the sustained release of the active ingredient.

[0066] For example, when the release sustaining agent in the present disclosure includes a water-insoluble substance and / or a poorly water-soluble substance, the water-insoluble substance and / or the poorly water-soluble substance may be used in combination with a water-soluble substance, but is not limited thereto. In the present disclosure, the release sustaining agent includes known release sustaining agents, such as methacrylic acid copolymers, polyethylene oxide, cellulose acetate, copovidone, hydroxypropyl ethyl cellulose, glyceryl distearate, methyl cellulose, polyvinyl alcohol, ethyl cellulose, polyethylene glycol-polyvinyl alcohol copolymers, etc. Hydroxypropyl cellulose, hypromellose (hydroxypropyl methyl cellulose), microcrystalline cellulose, mannitol, sucrose, lactose, polyethylene glycol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, pregelatinized starch, natural gum, synthetic gum, polyvinyl pyrrolidone copolymer, povidone, gelatin, starch, highly dispersible silica, talc, or mixtures thereof, but is not limited thereto. Specifically, in the present disclosure, the release sustaining agent may include, but is not limited to, one or more selected from polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol-polyvinyl alcohol copolymer, polyethylene oxide, methacrylic acid copolymer, hydroxypropyl methylcellulose, ethylcellulose, povidone, talc, or mixtures thereof. In an example of the present disclosure, the release sustaining agent may include at least one selected from the group consisting of polyvinyl alcohol, polyethylene oxide, methacrylic acid copolymer, hydroxypropyl methylcellulose, ethylcellulose, povidone, and talc. In another example of the present disclosure, the release sustaining agent may include one or more selected from the group consisting of polyethylene oxide, methacrylic acid copolymer, polyvinyl alcohol, ethylcellulose, povidone, and talc.

[0067] In the embodiment of the present disclosure, the release sustaining agent may be included inside and / or outside the core. When the release sustaining agent is included inside the core, the core may be a mixture of the active ingredient, the release sustaining agent, and the pharma- ceutically acceptable additive, and the active ingredient, the release sustaining agent, and the pharma- ceutical acceptable additive may be present throughout the core, for example, mixed in the form of a single matrix. For example, when the core is a pellet, the core may include the release sustaining agent in an active ingredient layer formed on an inert particle, when the core is a granule, the core may include the release sustaining agent together with the active ingredient inside the granule, and when the core is a tablet, the release sustaining agent may be included inside the tablet. In addition, when the release sustaining agent is included outside the core, the release sustaining agent may be formed in the core so as to surround the core. For example, when the core is a pellet, the pellet may include a release sustaining agent (containing) layer formed on the active ingredient layer. When the core is a granule, the granule may include a release sustaining agent (containing) layer formed on the granule and surrounding the granule. When the core is a tablet, the tablet may include a release sustaining agent (containing) layer formed on the tablet.

[0068] The release sustaining layer may contain a pharma- ceutically acceptable additive, such as, but not limited to, talc. The content and type of the pharma- ceutically acceptable additive contained in the release sustaining layer can be appropriately selected by one skilled in the art.

[0069] When the modified release pharmaceutical composition of the present disclosure includes a release sustaining layer, the release sustaining layer may be included in an amount of about 10-70% by weight, specifically about 10-50% by weight, more specifically about 10-40% by weight, and even more specifically about 10-30% by weight, based on the total weight of the composition.

[0070] The modified release pharmaceutical compositions of the present disclosure may also include an enteric agent.

[0071] In the present disclosure, an enteric-coated agent refers to a substance that does not dissolve in the stomach but dissolves upon reaching the intestine, for example, the duodenum, etc. Specifically, the enteric-coated agent may be a substance that does not dissolve in the pH environment of the stomach (pH 2 or less) but starts to dissolve in the pH environment of the intestine (pH 5 to 7.5).

[0072] In the present disclosure, the enteric coating agent may be one or more selected from known enteric coating agents. For example, the enteric coating agent may be ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, vinegar The polymer may be any one or more selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl butyrate phthalate, polyvinyl acetate, hydroxypropylmethyl acetate, dioxypropylmethylcellulose succinate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, and polymers thereof; shellac; and acrylic acid, methacrylic acid, or esters thereof, or copolymers formed therefrom, but is not limited thereto. Specifically, as copolymers formed from acrylic acid, methacrylic acid, or esters thereof, methacrylic acid-ethyl acrylate copolymers (e.g., Eudragit L30D-55 and L100-55), methacrylic acid copolymers L (e.g., Eudragit L100), methacrylic acid copolymers S (e.g., Eudragit S100), and methacrylic acid-methyl acrylate-methacrylic acid copolymers (e.g., Eudragit FS30D) can be used.

[0073] As used herein, the term "methacrylic acid copolymer L" refers to an anionic copolymer containing methacrylic acid and methyl methacrylate in a ratio of about 1:1, and has the IUPAC name poly(methyl methacrylate-co-methacrylic acid) 1:1.

[0074] As used herein, the term "methacrylic acid copolymer S" refers to an anionic copolymer containing methacrylic acid and methyl methacrylate in a ratio of about 1:2, and has the IUPAC name poly(methyl methacrylate-co-methacrylic acid) 1:2.

[0075] In the present disclosure, the enteric-coated agent may be a pH-dependent enteric-coated agent, examples of which include methacrylic acid-ethyl acrylate copolymer soluble at pH 5.5 or higher, methacrylic acid copolymer L soluble at pH 6.0 or higher, and methacrylic acid copolymer S soluble at pH 7.0 or higher.

[0076] As used herein, the term "pH-dependent" means that dissolution or dissolution of the enteric-coated agent begins in an environment above a certain pH.

[0077] As used herein, the term "pH-dependent solubility" means that the enteric agent dissolves in an environment above a certain pH.

[0078] According to one embodiment of the present disclosure, when the enteric coating mixture contains methacrylic acid copolymers L and S, the methacrylic acid copolymer L and the methacrylic acid copolymer S may be mixed in a weight ratio of 1:3 to 0.2, particularly, but not limited to, 1:1.5 to 1:0.4. According to another embodiment, when the enteric coating mixture contains methacrylic acid-ethyl acrylate copolymer and methacrylic acid copolymer S, the methacrylic acid-ethyl acrylate copolymer and the methacrylic acid copolymer S may be mixed in a weight ratio of 0.3:1 to 3:1, particularly, but not limited to, 0.5:1 to 2:1.

[0079] When the modified release pharmaceutical composition of the present disclosure contains an enteric-coated agent in the above-mentioned ratio, the active ingredient tegoprazan can be released with a delay, so that tegoprazan can exert a sufficient medicinal effect even after a certain time has passed after administration.

[0080] In examples of the present disclosure, the enteric-containing layer may be soluble at pH 5.0 or higher, pH 5.5 or higher, pH 6.0 or higher, or pH 6.5 or higher. According to one embodiment of the present disclosure, the release regulating layer may be pH-dependently soluble at pH 5.5 or higher. According to another embodiment, the release regulating layer may be pH-dependently soluble at pH 6.0 or higher. According to yet another embodiment, the release regulating layer may be pH-dependently soluble at pH 6.5 or higher. According to yet another embodiment, the release regulating layer may be pH-dependently soluble at pH 7.0 or higher.

[0081] As used herein, the terms "insoluble" or "poorly soluble" refer to the property of any substance not dissolving or barely dissolving in a solvent, and conversely, the term "soluble" refers to any substance that is highly soluble in a solvent.

[0082] In the pharmaceutical composition of the present disclosure, the enteric agent-containing layer may be contained in an amount of about 10 to 70% by weight, specifically about 10 to 50% by weight, more specifically about 10 to 40% by weight, and even more specifically about 10 to 30% by weight, based on the total weight of the composition.

[0083] In the embodiment of the present disclosure, when the composition contains an enteric-coated or enteric-coated-containing layer, it may be acid-resistant. Specifically, the dissolution rate of the active ingredient in a dissolution medium of pH 1.2 may be 10% or less in 120 minutes, more specifically, 5% or less in 120 minutes. Meanwhile, the dissolution rate of the active ingredient in a dissolution medium of pH 5 or more may be 50% or more, more preferably 60% or more, within 360 minutes.

[0084] The term "acid resistance" used in this specification refers to the case where the dissolution of the active ingredient under acidic conditions determined according to the guidelines for dissolution standards for oral drugs is 10% or less. In general, whether or not acid resistance is ensured can be determined by measuring whether or not the active ingredient is released for 2 hours under low pH conditions (generally pH 1 to 2).

[0085] In the present disclosure, the dissolution rate can be measured according to Pharmacopoeia Dissolution Test Method 1 (basket method) or Dissolution Test Method 2 (paddle method). Specifically, the dissolution test can be performed at a dissolution temperature of 36.5 to 37.5°C, a dissolution volume of 500 mL to 1000 mL, and a rotation speed of 75 rpm to 100 rpm. In the case of Dissolution Test Method 1, the rotation speed of the basket may preferably be 100 rpm, and in the case of Dissolution Test Method 2, the rotation speed of the paddle may preferably be 75 rpm.

[0086] The enteric-coated layer of the present disclosure may further contain pharma- ceutically acceptable additives. Examples of additives that may further be contained include, but are not limited to, binders, anti-adhesive agents, plasticizers, surfactants, disintegrants, and excipients. One or more pharma-ceutically acceptable additives may be contained in the release-modifying layer, and the content and type of the additives may be appropriately selected by those skilled in the art. For example, the enteric-coated layer may contain triethyl citrate, polysorbate, or a mixture thereof as a pharma-ceutically acceptable additive.

[0087] In the embodiment of the present disclosure, the pharmaceutical composition of the present disclosure may further comprise one or more additional layers containing only pharma- ceutically acceptable additives without active ingredients. The additional layer may facilitate the coating of the subsequent layer when the pharmaceutical composition is prepared by a method of forming multiple coating layers, or may function to prevent the ingredients contained in the two layers from directly contacting each other and interacting or causing a decrease in stability. The term "additional layer" may be used interchangeably with the term "separation layer" or "isolation layer" in the present disclosure.

[0088] According to examples of the present disclosure, the additional layer is disposed between the core and the release modifier-containing layer; and / or on the release modifier-containing layer. According to other examples of the present disclosure, when the pharmaceutical composition comprises two or more release modifier-containing layers, the additional layer may be disposed between the first release modifier-containing layer and the second release modifier-containing layer; and / or on the second release modifier-containing layer.

[0089] For example, when the core of the pharmaceutical composition is a tablet, the pharmaceutical composition may further include an additional layer between the tablet and the release modifier-containing layer and / or on the release modifier-containing layer. When the core of the pharmaceutical composition is in the form of an active ingredient layer formed on an inactive particle, the pharmaceutical composition may further include an additional layer between the inactive particle and the active ingredient layer; and between the active ingredient layer and the release modifier-containing layer; and / or on the release modifier-containing layer. In this case, when the inactive particle is made of or contains an organic acid and an additional layer is included between the inactive particle and the active ingredient layer, the additional layer can function as an isolation layer that suppresses contact between the organic acid and the active ingredient. In this case, the isolation layer can suppress contact between the active ingredient tegoprazan contained in the inactive particle and the organic acid, so that the stability of tegoprazan can be kept high, its storage stability can be improved, and the therapeutic effect of diseases mediated by acid pump antagonist activity can be improved.

[0090] According to one example of the present disclosure, in the modified release pharmaceutical composition of the present disclosure, an additional layer containing a pharma- ceutically acceptable additive not containing an active ingredient may be disposed on the core, and a release modifier-containing layer may be formed on the additional layer. According to another example of the present disclosure, in the modified release pharmaceutical composition of the present disclosure, an additional layer containing a pharma- ceutically acceptable additive not containing an active ingredient may be disposed on the inert particles, an active ingredient layer may be disposed on the additional layer, and a release modifier-containing layer may be disposed on the active ingredient layer. According to yet another example of the present disclosure, in the modified release pharmaceutical composition of the present disclosure, an active ingredient layer may be formed on the inert particles, and an additional layer containing only a pharma- ceutically acceptable additive not containing an active ingredient may be formed on the active ingredient layer. According to yet another example of the present disclosure, in the modified release pharmaceutical composition of the present disclosure, an additional layer containing a pharma- ceutically acceptable additive not containing an active ingredient may be formed on the inert particles, an active ingredient layer may be formed on the additional layer, an additional layer containing a pharma- ceutically acceptable additive not containing an active ingredient may be formed on the active ingredient layer, and a layer containing a release modifier may be formed on the additional layer. In the pharmaceutical composition of the present disclosure, if necessary, an additional layer containing a pharma- ceutically acceptable additive that does not contain an active ingredient may be formed on the release modifier layer of the above embodiment.When the inactive particles contain an organic acid, the additional layer formed between the inactive particles and the active ingredient layer may function as an isolation layer that suppresses contact between the organic acid and the active ingredient.

[0091] Additional layers may or may not be formed depending on the process and the type of materials contained in each layer.

[0092] In the examples of the present disclosure, the pharmaceutical composition may not include an additional layer, and the release modifier-containing layer in the pharmaceutical composition may function as a separator layer.

[0093] In an embodiment of the present disclosure, when a layer containing an organic acid is formed separately, an additional layer containing a pharma- ceutically acceptable excipient that does not contain an active ingredient may be disposed between the layer containing the organic acid and the layer containing the active ingredient, and function as an isolating layer that blocks contact between the organic acid and the active ingredient.

[0094] In the examples of the present disclosure, the additional layer containing a pharma- ceutically acceptable additive not containing an active ingredient may contain a polymer. The polymer may contain at least one compound selected from the group consisting of methylcellulose, ethylcellulose, hydroxymethylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, and polyethylene glycol. Specifically, the polymer may contain hypromellose. In this case, when the additional layer not containing an active ingredient contains hypromellose, the viscosity of the hypromellose in an aqueous solution at 25°C may be 5 to 50 m·Pas, preferably 3 to 15 m·Pas.

[0095] In the present disclosure, the additional layer that does not include an active ingredient may comprise a polymer in an amount of about 30-99 wt %, specifically about 35-90 wt %, and more specifically about 40-85 wt %, based on the total weight of the additional layer.

[0096] The additional layer not containing the active ingredient of the present disclosure may further contain a pharma- ceutically acceptable additive in addition to the polymer. Examples of additives that may further be contained include, but are not limited to, anti-adhesive agents, plasticizers, surfactants, disintegrants and excipients, and preferably, anti-adhesive agents and / or plasticizers. The content and type of pharma-ceutically acceptable additives can be appropriately selected by those skilled in the art. For example, the pharma-ceutically acceptable additive may be talc.

[0097] The preparation method of the pharmaceutical composition according to the present disclosure may be carried out according to a conventional process known in the pharmaceutical field. The coating according to this preparation method may be carried out by a general coating method known in the art, specifically, by using a fluidized bed pellet coater. For example, in the modified release pharmaceutical composition of the present disclosure, when the particles containing tegoprazan and / or a core are pellets and a release modifier layer (e.g., an enteric layer) is included on the core layer, the pharmaceutical composition of the present disclosure may be prepared by: i) spraying a coating solution prepared by dissolving the active ingredient in any solvent onto the inert particles, and then drying to form an active ingredient layer; and ii) spraying a coating solution prepared by dissolving the release modifier in any solvent onto the active ingredient layer. This method is for illustrative purposes only, and the preparation method of the pharmaceutical composition of the present disclosure is not limited thereto. In addition, when the pharmaceutical composition of the present disclosure contains a release modifier (e.g., a release sustaining agent) inside the active ingredient layer, the coating solution prepared by dissolving the active ingredient contains the release modifier, and the release solution containing the release modifier can be used to form the active ingredient layer. In addition, when the pharmaceutical composition of the present disclosure includes multiple release modifier layers, it can be prepared by spraying a coating solution prepared by dissolving the release modifier (second) in any solvent onto the release modifier (first) layer after spraying and drying the coating solution in step ii). Furthermore, the preparation method of the pharmaceutical composition of the present disclosure may further include a step of spraying and drying a coating solution for forming an isolation layer before spraying the coating solution in step i) and / or ii). The isolation layer formed by coating before spraying the coating solution of the active ingredient layer and / or the release modulating layer can spatially separate the layers from each other to prevent contact between the components contained in the layers and to enhance stability. In addition, the isolation layer can be advantageous in terms of ease of production (yield, content, etc.) by roughening the surface during processing or cleaning the surface during porous surface formation, thereby enabling the layer to be efficiently formed to be coated thereafter, and can be useful in improving the wear resistance of the pharmaceutical composition.

[0098] In the present disclosure, the solvent of the coating solution can be selected from, but is not limited to, for example, ethanol, purified water, isopropyl alcohol, acetone, and mixtures thereof. The coating solution may contain pharma- ceutically acceptable additives, including, but not limited to, binders, plasticizers, anti-adherents, surfactants, disintegrants, excipients, or mixtures thereof.

[0099] In embodiments of the present disclosure, the modified release pharmaceutical composition may be a capsule, tablet, pellet, or granule.

[0100] In the embodiment of the present disclosure, when the pharmaceutical composition is a pellet, the pellet may include a core containing inert particles and an active ingredient-containing coating layer formed on the inert particles. The active ingredient-containing coating layer may include a release modifier. In one embodiment, the pellet may be a pellet having a release modifier-containing layer formed on the core. The release modifier-containing layer may be one or more, and when the release modifier-containing layer has two or more layers, the release modifiers contained in adjacent layers may be different from each other. The release modifier contained in the active ingredient layer and the release modifier in the release modifier layer formed on the core may each independently be a release modifier, an enteric agent, or both. In one embodiment, the release modifier contained in the active ingredient layer may be a release modifier, and the release modifier in the release modifier-containing layer may be an enteric agent. In another embodiment, when the release modifier-containing layer comprises two layers, the pharmaceutical composition comprises a core; a first release modifier-containing layer formed on the core; and a second release modifier-containing layer formed on the first release modifier-containing layer, where the first release modifier can be a release sustaining agent and the second release modifier can be an enteric agent. Here, an additional layer that does not contain an active ingredient can be included between the inactive particles, the active ingredient-containing layer (active ingredient layer), the core, and the release modifier layer. Here, the active ingredient-containing layer and the release modifier-containing layer can contain a pharma- ceutically acceptable additive. In this case, the inactive particles, the active ingredient, the active ingredient-containing layer, the release modifier, the release sustaining agent, the enteric agent, the release modifier-containing layer, the additional layer that does not contain an active ingredient, and the pharma-ceutically acceptable additive are the same as those described above unless otherwise stated.

[0101] In the embodiment of the present disclosure, when the pharmaceutical composition is a granule, the granule may be a granule comprising a core containing an active ingredient; and a release modifier-containing layer formed on the core. In this case, an additional layer not containing an active ingredient may be included between the core and the release modifier-containing layer. Alternatively, the granule may be a granule (wet granule or dry granule) formed from a mixture containing an active ingredient and a pharma- ceutically acceptable additive. In this case, a release modifier-containing layer may be formed on the core, which is a granule. In this case, a layer not containing an active ingredient may be further included between the core and the release modifier-containing layer. Alternatively, the granule may be a granule (wet granule or dry granule) formed from a mixture containing an active ingredient, a pharma- ceutically acceptable additive, and a release modifier. In this case, a release modifier layer may be included on the core, which is a granule. In the above-mentioned granule, the release modifier-containing layer may be one or more, and when the release modifier-containing layer has two or more layers, the release modifiers contained in each layer may be different from each other. Here, the inert particles, active ingredient, active ingredient-containing layer, release modifier, release modifier-containing layer, additional layer not containing an active ingredient, and pharma- ceutically acceptable excipients are the same as those described above, unless otherwise inconsistent.

[0102] In the embodiment of the present disclosure, when the pharmaceutical composition is a tablet, the tablet may be a tablet containing an active ingredient, and in this case, the tablet may be a core tablet formed by compressing granules or pellets containing a pharma- ceutically acceptable additive. Here, the core tablet may contain a release modifier. Furthermore, the tablet may be a tablet having a release modifier-containing layer formed on the core tablet. For example, the tablet may be formed by compressing granules containing an active ingredient, and the granules may include either a core containing an active ingredient or a release modifier-containing layer disposed on the core. In this case, the core containing the active ingredient may be a granule (wet granule or dry granule) formed from a mixture containing the active ingredient and a pharma- ceutical acceptable additive, and may further contain a release modifier. Alternatively, the tablet may be a tablet formed by compressing granules (wet granule or dry granule) formed from a mixture containing the active ingredient, a pharma- ceutical acceptable additive, and a release modifier. The tablet may further include a release modifier on the tablet. In this case, a layer containing a pharma- ceutically acceptable additive not containing an active ingredient may be further included between the core and the release modifier-containing layer, where the granules, pellets, active ingredient, active ingredient-containing layer, release modifier, release modifier-containing layer, additional layer not containing an active ingredient, and pharma- ceutically acceptable additive are the same as those described above unless otherwise stated.

[0103] The modified release pharmaceutical compositions according to the present disclosure may be formulated as oral dosage forms.

[0104] In the present disclosure, the release-modifying composition may be formulated as a capsule. In this case, the capsule may be filled with tablets, granules, pellets, or mixtures thereof, where the tablets, granules, and pellets are as described above. In this case, the capsule may further contain a powder that is the active ingredient itself, or a mixture of the active ingredient and a pharma- ceutically acceptable additive, or a mixture of the active ingredient, a pharma- ceutical acceptable additive, and a release-modifying agent. For example, the capsule may be filled with pellets, tablets, or granules, or a mixture of powder and pellets, a mixture of powder and granules, a mixture of powder and tablets, a mixture of pellets and tablets, a mixture of pellets and granules, or a mixture of tablets and granules. Or, a mixture of powder, pellets, and tablets, a mixture of powder, pellets, and granules, a mixture of powder, granules, and pellets, a mixture of pellets, tablets, and granules, or a mixture of powder, pellets, tablets, and granules.

[0105] According to an embodiment of the present disclosure, the capsule may be filled with pellets. For example, the capsule may be a capsule filled with pellets including inert particles and an active ingredient-containing coating layer formed on the inert particles, the active ingredient-containing coating layer including a release modifier on the active ingredient-containing layer and / or a release modifier-containing layer formed on the core.

[0106] In the present disclosure, the release-improving composition may be formulated as a tablet. The tablet may be a tablet comprising a core comprising inert particles and an active ingredient-containing coating layer formed on the inert particles; and a release modifier-containing layer formed on the core, in which case the inert particles may be a core tablet formed by tableting granules containing pharma- ceutically acceptable additives. Alternatively, the tablet may be formed by tableting granules, pellets, or a mixture thereof, in which case the granules and pellets are as described above. Here, the tablet may further comprise a powder that is the active ingredient itself. For example, the tablet may be formed by tableting granules containing the active ingredient, in which case the granules may comprise a core containing the active ingredient, may comprise a release modifier on the core, and / or may comprise a release modifier-containing layer disposed on the core. In this case, the core containing the active ingredient may be a granule (wet granule or dry granule) formed from a mixture containing the active ingredient and a pharma-ceutically acceptable additive, and if the core comprises a release modifier, the mixture may further comprise a release modifier. Alternatively, the tablet may be formed by compressing granules (wet or dry) formed from a mixture containing the active ingredient, pharma- ceutically acceptable excipients and release modifiers.

[0107] When the modified release pharmaceutical composition of the present disclosure contains both a sustained release agent and an enteric coating, the modified release pharmaceutical composition of the present disclosure may be in a form in which the sustained release portion containing the active ingredient and the sustained release agent and the enteric coating portion containing the active ingredient and the enteric coating are separated.For example, when the pharmaceutical composition is a capsule, the capsule contains the sustained release portion containing the active ingredient and the sustained release agent; and the enteric coating portion containing the active ingredient and the enteric coating, and the sustained release portion and the enteric coating portion may be independently powder, granule, pellet or tablet, and the sustained release portion and the enteric coating portion may be independently powder, granule, pellet or tablet, and the capsule may be filled with the sustained release portion and the enteric coating portion which are independently powder, granule, pellet or tablet.Alternatively, in the pharmaceutical composition of the present disclosure, the active ingredient, the sustained release agent and the enteric coating may be in the form of a single particle (granule, pellet or tablet).

[0108] The modified release pharmaceutical composition of the present disclosure may further include a pharma- ceutically acceptable additive. The pharma- ceutically acceptable additive of the present disclosure may include, but is not limited to, a binder, an anti-adhesive agent, a plasticizer, a surfactant, a stabilizer, a disintegrant, and an excipient. The active ingredient layer may include one or more additives, and the content and type of the additives may be appropriately selected by a person skilled in the art within a range that does not affect the stability or effect of the active ingredient. Examples of binders include, but are not limited to, polyvinyl alcohol, ethyl cellulose, polyethylene glycol-polyvinyl alcohol copolymer, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose), microcrystalline cellulose, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, sodium carboxymethylcellulose, gelatinized starch, natural gum, synthetic gum, polyvinylpyrrolidone copolymer, povidone, gelatin, starch, or highly dispersible silica. Examples of anti-adhesion agents include, but are not limited to, light anhydrous silicic acid, hydrous silicon dioxide, talc, or stearic acid. Examples of plasticizers include, but are not limited to, acetyl triethyl citrate, triethyl citrate, diethyl phthalate, polyethylene glycol, or triacetin. However, hydrophilic and highly reactive plasticizers such as polyethylene glycol may affect long-term stability, so they may not be added depending on the purpose. Examples of surfactants include, but are not limited to, sodium lauryl sulfate, polyethylene, glycol, poloxamer, polysorbate (polysorbate 20, 40, 60, or 80). Examples of stabilizers include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, synthetic hydrotalcite, and magnesium aluminum hydroxide.Examples of disintegrants include, but are not limited to, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, algins such as sodium alginate and alginic acid, celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose, crosslinked celluloses such as carmellose and croscarmellose sodium, gums such as guar gum and xanthan gum, and foaming agents such as sodium bicarbonate and citric acid.

[0109] The modified release pharmaceutical compositions of the present disclosure may be used for the prevention or treatment of diseases mediated by acid pump antagonist activity.

[0110] The present disclosure provides a modified release pharmaceutical composition of the present disclosure for the prevention or treatment of a disease condition mediated by acid pump antagonist activity.

[0111] Diseases mediated by acid pump antagonist activity include, but are not limited to, 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, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, or asthma, preferably gastroesophageal reflux disease (GERD).

[0112] Gastroesophageal reflux disease (GERD) is a condition in which stomach contents reflux into the esophagus, causing symptoms and complications that interfere with daily life. GERD can be classified as erosive esophagitis (EE) and non-erosive reflux disease (NERD).

[0113] As used herein, "prevention" includes preventing, delaying, or suppressing the onset of a disease, and "treatment" includes alleviating disease symptoms, preventing the worsening of a disease, and delaying or suppressing a disease.

[0114] The modified release pharmaceutical composition of the present disclosure can regulate the release of the active ingredient tegoprazan, and therefore can maintain a high concentration of tegoprazan in the blood for a certain period of time after administration. Therefore, the modified release pharmaceutical composition can exert an excellent therapeutic effect on the above-mentioned diseases for a long period of time, and can significantly improve the patient's compliance with medication. In addition, the pharmaceutical composition exhibits excellent storage stability when formulated, and further exhibits excellent dissolution properties even in an environment having a higher pH than the gastric fluid environment, and as a result, can exhibit excellent dissolution properties in an intestinal fluid environment, for example, in the duodenal environment. In addition, the pharmaceutical composition can achieve a therapeutically excellent blood concentration of tegoprazan without decreasing the dissolution rate of tegoprazan by regulating the solubility, even when the release of tegoprazan is delayed, and the pharmaceutical composition can achieve an excellent sustained release of tegoprazan even in an intestinal fluid environment.

[0115] The present disclosure provides the use of the modified release pharmaceutical composition of the present disclosure for the prevention or treatment of a disease mediated by acid pump antagonist activity.

[0116] The present disclosure provides the use of a modified release pharmaceutical composition of the present disclosure in the manufacture of a medicament for the prevention or treatment of a disease mediated by acid pump antagonist activity.

[0117] The present disclosure provides a method for preventing or treating a disease mediated by acid pump antagonism activity, the method comprising administering to a subject in need thereof an effective amount of a modified release pharmaceutical composition of the present disclosure.

[0118] In this disclosure, the term "subject" refers to a mammal, including, but not limited to, a human, guinea pig, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, or rabbit. Specifically, the subject may be a human.

[0119] The modified release pharmaceutical compositions in the above-mentioned uses and methods of prevention or treatment are the same as those described above, unless contradictory.

[0120] The modified release pharmaceutical compositions of the present disclosure may be used in combination with pharmaceutical compositions for immediate release of the active ingredient.

[0121] In this disclosure, the term "effective amount" as used herein refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the level of effective amount can be determined by including the type of disease, the severity of disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period and concurrently used drugs, and other factors well known in the medical technology.Taking all factors into consideration, it is important to administer the amount that obtains maximum effect with the minimum amount and does not cause side effects, and such amount can be determined by those skilled in the art.

[0122] formulation The present disclosure relates to A first pharmaceutical composition in modified release form comprising, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a second pharmaceutical composition containing tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient, and immediately releasing the active ingredient; The present invention provides a formulation comprising:

[0123] According to the present disclosure, immediate release and release regulation of tegoprazan from the formulation can be achieved, and rapid drug efficacy can be obtained, while maintaining a high blood concentration of tegoprazan for a certain time after taking the formulation. Therefore, the formulation of the present disclosure has an excellent therapeutic effect and can significantly improve the patient's compliance with medication. The formulation of the present disclosure may be in a form in which the active ingredient is released in a short time after taking the formulation, and then additional release of the active ingredient occurs after a certain time has passed. In this case, the blood concentration of tegoprazan may increase immediately after taking the formulation, and then the blood concentration of tegoprazan may increase again after a certain period of time (or at a specific location or under specific conditions). For example, tegoprazan may be rapidly released in a gastric fluid environment immediately after administration, so that the blood concentration of tegoprazan may increase rapidly, and after a certain period of time, the blood concentration of tegoprazan may increase again while tegoprazan is eluted from the formulation in an intestinal fluid environment such as the duodenum at a pH of 5 or more. That is, when tegoprazan is continuously or pulsatilely eluted from the formulation after administration of the formulation, the blood concentration of tegoprazan may be increased by 2-fold or more. Alternatively, the formulation of the present disclosure may be in a form in which the active ingredient is released shortly after administration, and then the active ingredient is continuously released for a certain period of time. In this case, the blood concentration of tegoprazan may increase immediately after taking the formulation, and the release of tegoprazan is sustained, so that the blood concentration of tegoprazan may also be maintained or increased. Alternatively, the formulation of the present disclosure may be in a form in which the active ingredient is released shortly after administration, and after a certain period of time (or under a specific position or condition), additional release of the active ingredient begins, and the release is sustained for a certain period of time thereafter. In this case, the blood concentration of tegoprazan may increase immediately after taking the formulation, and after a certain period of time, the blood concentration of tegoprazan increases again, and then the release of tegoprazan is sustained, so that the blood concentration of tegoprazan may be maintained or increased. For example, after drug administration, tegoprazan may be rapidly released immediately in the gastric fluid environment, causing the blood tegoprazan concentration to rise rapidly, and after a certain period of time, the blood tegoprazan concentration may also increase.For example, after drug administration, tegoprazan is rapidly released immediately in a gastric fluid environment, so that the blood tegoprazan concentration rises rapidly, and after a certain time has passed, in an intestinal fluid environment such as the duodenum having a pH of 5 or more, the blood tegoprazan concentration rises again while tegoprazan is being dissolved from the formulation, so that tegoprazan is continuously dissolved from the formulation for a certain period of time, and the blood tegoprazan concentration is maintained or increased. Thus, by administering the formulation of the present disclosure, even when the dosage of tegoprazan in the formulation is small, a sustained pharmacological effect in which the medicinal effect is rapidly exerted can be exhibited.

[0124] In the preparation containing the first modified release pharmaceutical composition of the present disclosure, the above-mentioned contents in the section "modified release pharmaceutical composition" can be applied in the same manner unless there is any contradiction.Therefore, the above-mentioned structure of the "modified release pharmaceutical composition", the above-mentioned inert particles, core, release modifier, release modifier-containing layer, release sustainer, release sustainer-containing layer, enteric coating, enteric coating-containing layer, pellet, tablet, granule, capsule, pharma- ceutical acceptable additive, components contained in the composition, and the content ratio of components can be applied in the same manner to the first modified release pharmaceutical composition unless there is any contradiction.

[0125] In the embodiment of the present disclosure, the second pharmaceutical composition, which provides immediate release of the active ingredient, may be appropriately formulated to provide immediate release of the active ingredient. In one example, the second pharmaceutical composition may include inert particles and an active ingredient layer containing the active ingredient disposed on the inert particles. In this case, an additional layer not containing the active ingredient but containing only pharma- ceutically acceptable additives may be included between the inert particles and the active ingredient layer, but is not limited thereto, and the additional layer may not be included. When an additional layer is included, the additional layer may have a function of facilitating the formation of a subsequent layer. The additional layer may be disposed between the inert particles and the active ingredient layer and / or on the active ingredient layer. The second pharmaceutical composition including the inert particles and the active ingredient layer may be a pellet. In another example, the second pharmaceutical composition may be a particle prepared from a mixture containing a pharma- ceutically acceptable additive and an active ingredient. For example, the second pharmaceutical composition may be a granule formed from a mixture containing an active ingredient and a pharma- ceutical acceptable additive. Alternatively, the second pharmaceutical composition may be a mixture of a pharma- ceutical acceptable additive and an active ingredient, and the mixture may be in the form of a powder. In yet another example, the second pharmaceutical composition may also be a tablet prepared from pellets, granules, powders, or mixtures thereof, wherein the inert particles, granules, pellets, powders, tablets, additional layers, the functions of the additional layers, the components and contents of the pharma- ceutically acceptable excipients are as described above for the "modified release pharmaceutical composition" unless otherwise inconsistent.

[0126] In embodiments of the present disclosure, the first pharmaceutical composition and the second pharmaceutical composition may be separate from one another and present as separate particles.

[0127] In embodiments of the present disclosure, the first pharmaceutical composition and the second pharmaceutical composition may each independently be a powder, pellets, granules, or tablets.

[0128] In embodiments of the present disclosure, the first pharmaceutical composition may be a pellet, granule, or tablet, where the pellet, granule, or tablet is as described above with respect to the "modified release pharmaceutical composition."

[0129] In the embodiment of the present disclosure, the second pharmaceutical composition may be a powder, pellet, granule, or tablet. In one example, the second pharmaceutical composition may be a powder, in which case the second pharmaceutical composition may be a mixture of an active ingredient and a pharma- ceutically acceptable additive. In another example, the second pharmaceutical composition may be a pellet. In this case, the pellet may include an inert particle and a coating layer containing an active ingredient disposed on the inert particle. The pellet may further include an additional layer that does not include an active ingredient and contains only a pharma- ceutically acceptable additive, and the additional layer may be disposed between the inert particle and the active ingredient layer and / or on the active ingredient layer. Here, the inert particle, the active ingredient, the layer containing the active ingredient, and the additional layer that does not include an active ingredient and contains only a pharma- ceutically acceptable additive are as described above with respect to the "modified release pharmaceutical composition" unless otherwise inconsistent.

[0130] In another example, the second pharmaceutical composition may be a granule, and the granule may include inert particles and a coating layer containing an active ingredient on the inert particles. Furthermore, the granule may be a granule (wet granule or dry granule) formed from a mixture containing an active ingredient and a pharma- ceutically acceptable additive. Here, the inert particles, the active ingredient, the pharma- ceutically acceptable additive, etc. are as described above for the "modified release pharmaceutical composition" unless otherwise inconsistent.

[0131] In another example, the second pharmaceutical composition may be a tablet, and the tablet may include inert particles and an active ingredient layer disposed on the inert particles. Here, the inert particles may be a core tablet formed by tableting granules or pellets containing pharma- ceutically acceptable additives. Alternatively, the tablet may be formed by tableting granules containing the active ingredient, and in this case, the granules may be granules (wet granules or dry granules) formed from a mixture containing the active ingredient and the pharma- ceutically acceptable additives. In this case, an additional layer not containing the active ingredient and consisting only of pharma- ceutically acceptable additives may be included between the inert particles and the active ingredient-containing layer and / or on the active ingredient-containing layer. Here, the inert particles, active ingredient, active ingredient-containing layer, additional layer not containing the active ingredient, etc. are as described above with respect to the "modified release pharmaceutical composition" unless there is a contradiction.

[0132] In embodiments of the present disclosure, the formulation may be formulated as an oral dosage form.

[0133] Furthermore, when the first pharmaceutical composition and the second pharmaceutical composition exist as separate particles separated from each other, the first pharmaceutical composition and the second pharmaceutical composition can be formulated as a single unit dosage form or as respective unit dosage forms.

[0134] In addition, when the first pharmaceutical composition and the second pharmaceutical composition are formulated as respective unit dosage forms, the unit dosage form of the first pharmaceutical composition and the unit dosage form of the second pharmaceutical composition can be administered simultaneously. The unit dosage form of the first pharmaceutical composition can be a powder, pellet, granule or tablet, or a capsule filled with pellets, granules or tablets, and the unit dosage form of the second pharmaceutical composition can be a powder, pellet, granule or tablet, or a capsule filled with powder, pellet, granule or tablets, and the unit dosage form of the first pharmaceutical composition and the unit dosage form of the second pharmaceutical composition can be independent of each other. Here, the powder, pellet, granule, tablet and capsule can be the same as those described above, unless there is a contradiction.

[0135] The first and second pharmaceutical compositions can be formulated as a single unit dosage form.

[0136] In the examples of the present disclosure, the formulation can be formulated as a capsule.

[0137] In the embodiment of the present disclosure, when the first pharmaceutical composition and the second pharmaceutical composition are in the form of separate particles, the formulation may be a capsule filled with the first pharmaceutical composition and the second pharmaceutical composition. In this case, the first pharmaceutical composition and the second pharmaceutical composition may each independently be a powder, pellet, granule, or tablet, and may be in the same form or different forms. Here, the powder, pellet, granule, or tablet are as described above. For example, the formulation may be a capsule filled with a first pharmaceutical composition in the form of a pellet, and a second pharmaceutical composition in the form of a pellet, from which the active ingredient is immediately released. Alternatively, the formulation may be a capsule filled with a first pharmaceutical composition in the form of a pellet, and a second pharmaceutical composition in the form of a tablet or granule, from which the active ingredient is immediately released. Here, the first pharmaceutical composition in the form of a pellet, granule, or tablet is as described above for the "modified release pharmaceutical composition," and the second pharmaceutical composition in the form of a powder, pellet, granule, or tablet is as described above.

[0138] In embodiments of the present disclosure, when the formulation is a capsule, the first pharmaceutical composition may be a pellet and the second pharmaceutical composition may be a powder, granules or tablet.

[0139] In one embodiment, the first pharmaceutical composition, which is a pellet, may comprise inert particles; an active ingredient layer containing an active ingredient formed on the inert particles; and a release modifier (containing) layer containing a release modifier formed on the active ingredient layer. The release modifier may be at least one selected from the group consisting of a release sustaining agent and an enteric agent.

[0140] In another embodiment, the first pharmaceutical composition, which is a pellet, may include an active ingredient layer formed on an inert particle, the active ingredient layer including a first release modifier; and a second release modifier (containing) layer formed on the active ingredient layer, the second release modifier. The first and second release modifiers may each independently be at least one selected from the group consisting of a release sustaining agent and an enteric agent. For example, the first release modifier may be a release sustaining agent and the second release modifier may be an enteric agent.

[0141] In yet another embodiment, the first pharmaceutical composition, which is a pellet, may comprise an active ingredient layer formed on an inert particle, the active ingredient layer comprising an active ingredient and a first release modifier; a second release modifier (containing) layer formed on the active ingredient layer, the second release modifier (containing) layer comprising a second release modifier; and a third release modifier (containing) layer formed on the second release modifier (containing) layer, the third release modifier (containing) layer comprising a third release modifier. The first, second and third release modifiers may each independently be at least one selected from the group consisting of a release sustaining agent and an enteric agent. For example, the first release modifier and the second release modifier may be a release sustaining agent, the third release modifier may be an enteric agent, and the first release modifier and the second release modifier may be the same or different from each other.

[0142] In one embodiment, the second pharmaceutical composition, which is a powder, may be a powdery mixture that is a mixture of an active ingredient and a pharma- ceutically acceptable additive. In this case, the powdery mixture may be distinguished from granules. In another embodiment, the second pharmaceutical composition, which is a granule, may be a granule prepared by a granulation process from a mixture containing an active ingredient and a pharma- ceutically acceptable additive.

[0143] Here, the pellets, inert particles, release modifiers, release sustaining agents, enteric coating agents, granules, powders, and pharma- ceutically acceptable additives are as described above.

[0144] In the examples of the present disclosure, the formulation can be formulated as a tablet.

[0145] In the example of the present disclosure, when the first pharmaceutical composition and the second pharmaceutical composition are in the form of separate particles, the formulation may be a tablet comprising the first pharmaceutical composition and the second pharmaceutical composition. In one embodiment, the tablet may be a multi-layer tablet comprising a first layer comprising the first pharmaceutical composition and a second layer comprising the second pharmaceutical composition, where the first layer may release the active ingredient in a modified manner (e.g., delayed manner, sustained manner, or both) and the second layer may release the active ingredient immediately. Here, the tablet may be prepared by compressing the first pharmaceutical composition in the form of granules or pellets and the second pharmaceutical composition in the form of powder, granules or pellets. In another embodiment, the tablet may be a multi-layer tablet in the form of a tablet-in-tablet (tab-in-tab) comprising a first layer, which is a core tablet comprising the first pharmaceutical composition, and a second layer, which surrounds the first layer and comprises the second pharmaceutical composition. In this case, the tablet can be prepared by compressing a first pharmaceutical composition in the form of granules or pellets to prepare a core tablet, and compressing the core tablet with a second pharmaceutical composition in the form of powder, granules or pellets, where the first pharmaceutical composition in the form of pellets or granules is as described above for the "modified release pharmaceutical composition" and the second pharmaceutical composition in the form of powder, pellets or granules is as described above.

[0146] When the first pharmaceutical composition in the form of pellets or granules contains an enteric coating, the formulation of the present disclosure in the form of a tablet prepared from the pellets or granules may release the active ingredient in a delayed manner from the first layer. When the first pharmaceutical composition in the form of pellets or granules contains a release sustaining agent, the formulation of the present disclosure in the form of a tablet prepared from the pellets or granules may release the active ingredient in a sustained manner from the first layer. When the first pharmaceutical composition in the form of pellets or granules contains an enteric coating and a release sustaining agent, the formulation of the present disclosure in the form of a tablet prepared from the pellets or granules may release the active ingredient in a delayed and sustained manner from the first layer.

[0147] In an example of the present disclosure, the first pharmaceutical composition and the second pharmaceutical composition may be present together within a single particle.

[0148] In embodiments of the present disclosure, the first pharmaceutical composition is as described above for a "modified release pharmaceutical composition" and the second pharmaceutical composition may be disposed on the first pharmaceutical composition.

[0149] In an embodiment of the present disclosure, the first pharmaceutical composition comprises a core containing an active ingredient, a release modifier on the core, and / or a release modifier layer containing a release modifier disposed on the core, where the second pharmaceutical composition may be disposed on the core or on the release modifier layer formed on the core. In this case, the formulation comprising the first pharmaceutical composition and the second pharmaceutical composition may further comprise an additional layer that does not contain an active ingredient and consists only of pharma- ceutically acceptable excipients. The function of the additional layer and the substances contained therein are as described above for the "modified release pharmaceutical composition."

[0150] When the above-mentioned formulation is administered, the active ingredient in the second pharmaceutical composition outside the formulation dissolves in a gastric fluid environment, and when the release modifier dissolves from the first pharmaceutical composition, the active ingredient may dissolve in a region from the gastric fluid environment to the intestinal environment, or may dissolve in an intestinal environment other than the gastric fluid environment (e.g., the duodenum), or may dissolve in an intestinal environment other than the gastric fluid environment and dissolve continuously for a certain period of time.

[0151] In embodiments of the present disclosure, when the first pharmaceutical composition and the second pharmaceutical composition are present together in a single particle, the particle may be a granule, pellet, or tablet.

[0152] In the embodiment of the present disclosure, when the particle is a pellet, the pellet may include a core including an inert particle and a coating layer including an active ingredient and a release-sustaining agent formed on the inert layer; an enteric-containing layer provided on the core; and an active ingredient layer including an active ingredient disposed on the enteric-containing layer. In this case, an additional layer not including an active ingredient may be included between the inert particle, the coating layer including an active ingredient, the core, and the enteric-containing layer. When an additional layer is included between the core and the enteric-containing layer, the additional layer may be a release-sustaining agent-containing layer including a release-sustaining agent. Here, the inert particle, the active ingredient, the coating layer including an active ingredient, the release-sustaining agent, the enteric-containing layer, the release-sustaining agent-containing layer, and the additional layer not including an active ingredient are as described above with respect to the "modified release pharmaceutical composition" unless otherwise stated.

[0153] In the embodiment of the present disclosure, when the particle is a granule, the granule may include a core including inert particles and a coating layer including an active ingredient and a release sustaining agent formed on the inert particles; an enteric-containing layer on the core; and an active ingredient layer including the active ingredient disposed on the enteric-containing layer. Alternatively, the granule may include a core that is a granule (wet granule or dry granule) formed from a mixture including an active ingredient, a release sustaining agent, and a pharma- ceutically acceptable excipient; an enteric-containing layer disposed on the core; and an active ingredient layer including the active ingredient disposed on the enteric-containing layer. Alternatively, the granule may include a granule (wet granule or dry granule) formed from a mixture including at least one of an active ingredient, a pharma- ceutically acceptable excipient, a release sustaining agent, and an enteric coating; and an active ingredient layer including the active ingredient disposed on the granule. In this case, an additional layer not including an active ingredient may be included between the inert particles, the active ingredient-containing layer, the core, and the enteric-containing layer. When an additional layer is included between the core and the enteric-containing layer, the additional layer may be a release sustaining agent-containing layer that includes a release sustaining agent. Herein, the inert particles, active ingredient, active ingredient-containing layer, release-sustaining agent, enteric agent, enteric agent-containing layer, release-sustaining agent-containing layer, and any additional layers not containing an active ingredient are as described above for "modified release pharmaceutical composition" unless otherwise contradictory.

[0154] In the embodiment of the present disclosure, when the particle is a tablet, the tablet may include a core containing inert particles; an active ingredient layer containing an active ingredient and a release-sustaining agent formed on the inert particles; an enteric-containing layer disposed on the core; and an active ingredient layer containing the active ingredient disposed on the enteric-containing layer. In this case, the inert particles may be a core tablet formed by compressing granules or pellets containing a pharma- ceutically acceptable excipient. Alternatively, the tablet may include a core tablet formed by compressing granules containing an active ingredient and a release-sustaining agent; an enteric-containing layer disposed on the core tablet; and an active ingredient layer containing the active ingredient disposed on the layer. In this case, the granule may be a granule (wet granule or dry granule) prepared from a mixture of the active ingredient and a pharma-ceutically acceptable excipient. Alternatively, the tablet may include a core tablet formed by compressing granules (wet granule or dry granule) formed from a mixture containing the active ingredient, a pharma-ceutically acceptable excipient, and an enteric agent; and an active ingredient layer containing the active ingredient disposed on the core tablet. Here, an additional layer of a pharma- ceutically acceptable additive that does not contain an active ingredient may be further included between the inactive particles, the layer containing an active ingredient, the core, and the layer containing an enteric agent. When an additional layer is included between the core (core tablet) and the enteric agent-containing layer, the additional layer may be a release-prolonging agent-containing layer that contains a release-prolonging agent. Here, the inactive particles, the active ingredient, the active ingredient-containing layer, the release-prolonging agent, the enteric agent, the enteric agent-containing layer, the release-prolonging agent-containing layer, and the additional layer that does not contain an active ingredient are as described above for the "modified release pharmaceutical composition" unless otherwise stated.

[0155] In the present disclosure, the formulation may be a capsule.In this case, the capsule may be filled with powder, tablet, granule, pellet, or a mixture thereof, where the powder, tablet, granule, and pellet are as described above.For example, the capsule may be filled with each of the powder, pellet, tablet, and granule, or may be filled with a mixture of two or more of the powder, tablet, pellet, and granule.

[0156] According to embodiments of the present disclosure, the capsule may be filled with pellets. For example, the capsule may include a core including inert particles and a coating layer including an active ingredient and a release sustaining agent formed on the inert particles; an enteric-containing layer on the core; and an enteric-containing layer It may also be a capsule filled with pellets containing a layer containing the active ingredient disposed thereon.

[0157] In the present disclosure, the formulation may be a tablet. The tablet may be prepared by compressing powder, granules, pellets, or a mixture thereof, where the powder, pellets, or granules are as described above unless otherwise stated. For example, the tablet may be a multi-layer tablet including a core including inert particles and a coating layer including an active ingredient and a release-sustaining agent formed on the inert particles; an enteric-containing layer formed on the core; and an active ingredient layer including the active ingredient disposed on the layer. In this case, the inert particles may be a core tablet formed by compressing granules containing a pharma- ceutically acceptable additive. Alternatively, the tablet may include a core tablet formed by compressing granules containing an active ingredient and a release-sustaining agent; an enteric-containing layer disposed on the core; and an active ingredient layer including the active ingredient disposed on the enteric-containing layer. In this case, the granule may be a granule (wet granule or dry granule) prepared from a mixture of an active ingredient, a release-sustaining agent, and a pharma-ceutically acceptable additive. Alternatively, the tablet may be formed by compressing granules (wet or dry) formed from a mixture containing the active ingredient, pharma- ceutically acceptable excipients and an enteric agent.

[0158] In an embodiment of the present disclosure, the weight ratio between the active ingredient contained in the first pharmaceutical composition and the second pharmaceutical composition may be about 5:1 to 1:5 (weight:weight) as tegoprazan (free base form), specifically about 3:1 to 1:3 (weight:weight). In an embodiment of the present disclosure, the weight ratio between tegoprazan in the first pharmaceutical composition and tegoprazan in the second pharmaceutical composition may be 2:1 to 1:2. In an embodiment of the present disclosure, the weight ratio between tegoprazan in the first pharmaceutical composition and tegoprazan in the second pharmaceutical composition may be 2:1 to 1:1.

[0159] In an embodiment of the present disclosure, the formulation may contain tegoprazan (free base form) as an active ingredient in an amount of 10 mg to 200 mg, specifically 15 mg to 150 mg, per unit dosage form. For example, a first modified release pharmaceutical composition in the formulation may contain tegoprazan (free base form) as an active ingredient in an amount of about 5 mg to 100 mg per unit dosage form, and a second immediate release pharmaceutical composition may contain tegoprazan (free base form) as an active ingredient in an amount of about 5 mg to 100 mg per unit dosage form.

[0160] In the formulation of the present disclosure, the first pharmaceutical composition and the second pharmaceutical composition may be included in the formulation in a suitable ratio range. According to an embodiment of the present disclosure, the weight ratio of the first pharmaceutical composition to the second pharmaceutical composition included in the formulation may be about 10:1 to 1:10, preferably about 7:1 to 1:7, more preferably about 5:1 to 1:5. In an example of the present disclosure, the weight ratio of the first pharmaceutical composition to the second pharmaceutical composition may be 3:1 to 1:3, or 2:1 to 1:2.

[0161] In the present disclosure, the formulation may further include a pharma- ceutically acceptable additive. The pharma- ceutically acceptable additive may be included in the first pharmaceutical composition, or the second pharmaceutical composition, or the first and second pharmaceutical compositions, or may be included outside the first pharmaceutical composition and the second pharmaceutical composition. Examples of additives include, but are not limited to, binders, anti-adhesion agents, plasticizers, surfactants, stabilizers, disintegrants, excipients, etc. The active ingredient layer may contain one or more additives, and the content and type of the additives may be appropriately selected by a person skilled in the art within a range that does not affect the stability or effect of the active ingredient. The additives contained in the first pharmaceutical composition and the additives contained in the second pharmaceutical composition may be the same or different from each other. Examples of binders include, but are not limited to, polyvinyl alcohol, ethyl cellulose, polyethylene glycol-polyvinyl alcohol copolymer, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose), microcrystalline cellulose, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, sodium carboxymethylcellulose, gelatinized starch, natural gums, synthetic gums, polyvinylpyrrolidone copolymers, povidone, gelatin, starch, or highly dispersible silica. Examples of anti-adhesive agents include, but are not limited to, light anhydrous silicic acid, hydrated silicon dioxide, talc, or stearic acid. Examples of plasticizers include, but are not limited to, acetyl triethyl citrate, triethyl citrate, diethyl phthalate, polyethylene glycol, or triacetin. However, hydrophilic and highly reactive plasticizers such as polyethylene glycol may not be added depending on the purpose, as they may affect long-term stability. Examples of surfactants include, but are not limited to, sodium lauryl sulfate, polyethylene, glycol, poloxamer, polysorbate (polysorbate 20, 40, 60, or 80).Examples of stabilizers include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, synthetic hydrotalcite, and magnesium aluminum hydroxide. Examples of disintegrants include, but are not limited to, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, algins such as sodium alginate and alginic acid, celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose, crosslinked celluloses such as carmellose and croscarmellose sodium, gums such as guar gum and xanthan gum, and foaming agents such as sodium bicarbonate and citric acid.

[0162] In the present disclosure, a formulation comprising the first pharmaceutical composition and the second pharmaceutical composition may be used for the prevention or treatment of a disease mediated by acid pump antagonist activity.

[0163] The present disclosure provides a formulation of the present disclosure comprising a first pharmaceutical composition and a second pharmaceutical composition for the prevention or treatment of a disease mediated by acid pump antagonist activity.

[0164] Formulations comprising the first and second pharmaceutical compositions according to the present disclosure are effective in treating diseases mediated by acid pump antagonist activity, including, but not limited to, gastrointestinal diseases, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, or asthma.

[0165] The formulation comprising the first pharmaceutical composition and the second pharmaceutical composition according to the present disclosure contains an immediate release portion and a release control portion, and therefore can rapidly exert its medicinal effect while maintaining a high concentration of tegoprazan in the blood for a certain period of time after administration. Therefore, the formulation can exert an excellent therapeutic effect against the above-mentioned diseases, and can significantly improve the patient's compliance with medication. In addition, the formulation can exert a sufficient therapeutic effect against diseases mediated by acid pump antagonist activity even at a low dose, and therefore can reduce the side effects and maximize the therapeutic effect.

[0166] The present disclosure provides for the use of the formulations of the present disclosure for the prevention or treatment of diseases mediated by acid pump antagonist activity.

[0167] The present disclosure provides the use of a formulation of the present disclosure in the manufacture of a medicament for the prevention or treatment of a disease mediated by acid pump antagonist activity.

[0168] The present disclosure provides a method for preventing or treating a disease mediated by acid pump antagonism activity, the method comprising administering to a subject in need thereof an effective amount of a formulation of the present disclosure.

[0169] Use of the formulation of the present disclosure, and the prophylactic or therapeutic method using the formulation, are as described above unless otherwise stated.

[0170] As described above, the pharmaceutical composition of the present disclosure can maintain the therapeutic effect for a long time by controlling the release of the active ingredient, thereby improving the patient's compliance with medication. Therefore, the composition can be effectively used for diseases that require long-term administration of a drug or diseases that require the blood concentration of the drug to be maintained at a certain level or higher during the time period when the patient cannot take the drug.

[0171] In addition, the pharmaceutical composition of the present disclosure may contain an organic acid, which can increase the solubility of tegoprazan in the intestinal tract, maximize the therapeutic effect against diseases mediated by acid pump antagonist activity, and exhibit sufficient stability.

[0172] In addition, since the formulation of the present disclosure contains a modified release pharmaceutical composition and an immediate release pharmaceutical composition in a single dosage form, the blood concentration of the therapeutically effective amount of the active ingredient can be stably maintained for a long period of time, and the formulation can be effectively used for the treatment of diseases mediated by acid pump antagonistic activity.

[0173] In addition, since the formulation of the present disclosure contains a modified release pharmaceutical composition and an immediate release pharmaceutical composition in a single dosage form, the process time for its production can be shortened and the process efficiency can be increased. [Brief description of the drawings]

[0174] FIG. 1 is a schematic diagram of a tablet according to the present disclosure.

[0175] FIG. 2 shows the changes in plasma concentrations of tegoprazan in beagle dogs after oral administration of the modified release formulation of the present disclosure and the commercially available K-CABR tablet and immediate release formulation.

[0176] FIG. 3 is a graph showing the change in plasma concentration of tegoprazan in minipigs after oral administration of a formulation containing sugar-based sucrose and a formulation containing an organic acid as inert particles according to the present disclosure.

[0177] 4 is a graph showing the change in blood concentration of tegoprazan in monkeys after oral administration of a formulation containing sucrose as a carbohydrate and an organic acid as an inert particle according to the present disclosure.

[0178] The present disclosure will be described in more detail below with reference to examples. However, these examples are for the purpose of illustrating the present disclosure, and the scope of the present disclosure is not limited by these examples. Preparation Examples

[0179] To determine a suitable coating solution composition for coating tegoprazan, a coating solution was prepared using the active ingredient, various pharmaceutical excipients (binders, surfactants, anti-adherents, plasticizers, etc.) and solvents. [Table 1]

[0180] The coating solutions prepared above were confirmed to be suspended or partially dissolved in a pharmacopoeial solvent. Each prepared coating solution was thinly applied to a 150 mm petri dish, dried, and the solvent was evaporated. In this state, the coating layers were observed and it was confirmed that in the case of the coating solution in suspension form, a layer was formed with the active ingredient particles contained in the matrix structure of the conjugate, and in the case of the coating solution in solution form, a translucent or transparent layer was formed.

[0181] Examples 1 to 3 Prior to coating with an active ingredient layer containing tegoprazan, a separate inert coating (coating layer) was performed with each of the compositions shown in Table 2 below (hypromellose, polyethylene glycol, talc) in order to increase the stability of the active ingredient layer, efficiently form the coating layer, and increase wear resistance. [Table 2]

[0182] Specifically, sucrose-based spherical pellets (product name: Suglet, Colorcon) were used as inert particles, and a fluidized-bed pellet coater (GPCG-1, bottom spray, Glatt, Germany) was used for coating. The operating conditions of the fluidized-bed pellet coater were inlet air temperature 60 ± 10°C, exhaust flap pressure 0.6 ± 0.2 bar, and coating solution spray pressure 1.5 ± 0.6 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0183] After spraying the coating solution, the pellets were fluidized by supplying air at 75±10°C in a fluidized bed pellet coater and dried for about 30 to 120 minutes. Drying can be performed within the range of residual solvent allowed by the binder used, and can be performed by vacuum drying, oven drying, etc.

[0184] Examples 4 to 6 For coating an active ingredient layer containing tegoprazan, a coating solution having the composition shown in Table 3 below was prepared using pharma- ceutically acceptable additives and solvents. Then, using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany), a certain amount or the entire amount of the processed product including Example 1 or 3 was coated with the active ingredient layer on the outer surface. At this time, coating was performed so that one particle contained 25 to 200 mg. [Table 3]

[0185] The operating conditions of the fluidized bed pellet coater used for coating were: inlet air temperature 65 ± 10°C, exhaust flap pressure 0.7 ± 0.3 bar, coating solution spray pressure 1.5 ± 0.7 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while checking the fluidity according to the pellet loading amount.

[0186] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±10°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0187] Examples 7 to 9 In order to increase the stability of the active ingredient layer containing tegoprazan, to efficiently form a coating layer, and to increase abrasion resistance, a coating solution having the composition shown in Table 4 below was prepared, and an inert coating (coating layer) was applied to a certain amount or the entire outer surface of each of the processed products including Examples 4 to 6 using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 4]

[0188] The operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 60 ± 10°C, exhaust flap pressure 0.6 ± 0.2 bar, and coating solution spray pressure 1.5 ± 0.6 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0189] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±10°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0190] Examples 10 to 21 In order to ensure that a certain amount or the entire amount of the processed product including Example 7 or 8 had a delayed modified-release form, coating solutions having the compositions shown in Tables 5 and 6 below were prepared using pharma- ceutically acceptable additives and solvents, and delayed modified-release pellets were prepared using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 5] [Table 6]

[0191] When the solvent was purified water, the operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 60±10°C, exhaust air flap pressure 40±10 bar, and coating solution spray pressure 1.5±0.6 bar, and when the solvent was a mixture of purified water, alcohol, and acetone, the operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 35±10°C, exhaust air flap pressure 0.6±0.2 bar, and coating solution spray pressure 1.5±0.6 bar. In the coating solution spraying process, the partition height and the coating solution supply amount were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0192] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±1°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0193] Experimental example 1. Evaluation of dissolution under acidic conditions In order to eliminate the influence of the disintegration and disintegration time of the hard capsule, the pellets not filled in the capsule were weighed and the dissolution evaluation of Examples 7 to 9 was performed according to the United States Pharmacopeia (USP) Apparatus 1 (basket).

[0194] The elution conditions were set as follows: pH 1.2 (HCl buffer solution); 37 ± 0.5 °C; medium 900 ml; rotation speed 100 rpm. The sample solution obtained after the start of elution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies). [Table 7]

[0195] As can be seen from Table 7 above, in the cases of Examples 7 to 9 in which a delayed release adjusting layer was not applied, it was confirmed that tegoprazan was dissolved in a short period of time under acidic medium conditions, suggesting that the pellets of the present disclosure can be used as pellets for the immediate release of tegoprazan.

[0196] Experimental Example 2. Evaluation of acid resistance In order to eliminate the influence of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and the dissolution evaluation of Examples 10 to 21 was performed according to the United States Pharmacopeia (USP) Apparatus 1 (basket), and the acid resistance was evaluated.

[0197] The elution conditions were set as follows: pH 1.2 (HCl buffer solution); 37 ± 0.5 °C; medium 900 ml; rotation speed 100 rpm. The sample solution obtained after the start of elution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies). [Table 8]

[0198] As can be seen from Table 8 above, unlike Examples 7 to 9 which showed a high dissolution rate under acidic medium conditions because they did not contain a delayed release regulating layer, in the case of Examples 10 to 21 which contained a delayed release regulating layer, tegoprazan did not dissolve within 2 hours (120 minutes) under acidic medium conditions, or only a low dissolution rate was observed after 90 minutes, confirming that sufficient acid resistance was ensured.

[0199] Experimental Example 3. Evaluation of dissolution under weakly alkaline conditions After the acid resistance evaluation in Experimental Example 2 was completed, the elution property of the pellets including the modified release layer was evaluated in a weak alkaline medium.

[0200] The continuous dissolution test in this experimental example is a method by which a conventional engineer or a person skilled in the art and related persons can evaluate delayed release sustained dosage forms in a laboratory or in a test tube (in vitro). This method involves evaluating the dissolution in an acidic medium for a given time, followed by transferring the sample to a weakly alkaline medium or increasing the pH in the medium using an alkalizing agent. This method is used to evaluate the in vitro behavior of pharmaceutical products for quality control purposes (industry guidance, SUPAC-MR: Modified Release Solid Oral Dosage Form).

[0201] Specifically, after the acid resistance evaluation was completed, the basket containing the pellets (apparatus 1) was placed in a preheated pH 6.8 (phosphate buffer); 37 ± 0.5 °C; 900 ml of medium; and 100 rpm rotation speed, and the sample solution obtained after the start of the elution was analyzed using an ultraviolet spectrometer of a high performance liquid chromatography (HPLC; Agilent Technologies), and the results are shown in Table 9 below. [Table 9]

[0202] Examples 22 and 23 In order to enhance the stability of the active ingredient layer, efficiently form the coating layer, and enhance the abrasion resistance, a coating solution having the composition shown in Table 10 below (hypromellose 3 cps, hypromellose 6 cps, talc, and solvent) was prepared using additives and solvents, and each of the organic acid-containing inactive particle coating solutions was coated using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany) to form individual isolation layers, and the coating solution was coated using additives and solvents. [Table 10]

[0203] The operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 60 ± 10°C, exhaust flap pressure 0.6 ± 0.2 bar, and coating solution spray pressure 1.5 ± 0.6 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0204] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±10°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0205] Examples 24 to 28 For coating with an active ingredient layer containing tegoprazan, a coating solution having the composition shown in Table 11 below was prepared using pharmaceutical additives and solvents, and a certain amount or the entire outer surface of the processed products including Examples 22 or 23 was coated with each coating solution using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 11]

[0206] The operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 60 ± 10°C, exhaust flap pressure 0.7 ± 0.3 bar, and coating solution spray pressure 1.5 ± 0.7 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0207] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±10°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0208] Examples 29 and 30 In order to increase the stability of the active ingredient layer containing tegoprazan, to efficiently form a coating layer, and to increase abrasion resistance, a coating solution having the composition shown in Table 12 below was prepared, and an inert coating (coating layer) was applied to a certain amount or the entire outer surface of the processed products including Examples 24 to 25 using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 12]

[0209] The operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 60 ± 10°C, exhaust flap pressure 0.6 ± 0.2 bar, and coating solution spray pressure 1.5 ± 0.6 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0210] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±10°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0211] Examples 31 to 38 In order to ensure that a certain amount or the entire amount of the processed products including Examples 29 or 30 had a delayed release controlled form, a coating solution having the composition shown in Table 13 below was prepared using additives and solvents, and delayed release controlled pellets were prepared using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 13]

[0212] When the solvent was purified water, the operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 60±10°C, exhaust air flap pressure 40±10 bar, and coating solution spray pressure 1.5±0.6 bar, and when the solvent was a mixture of purified water, alcohol, and acetone, the operating conditions of the fluidized bed pellet coater used for coating were inlet air temperature 35±10°C, exhaust air flap pressure 0.6±0.2 bar, and coating solution spray pressure 1.5±0.6 bar. In the coating solution spraying process, the partition height and the coating solution supply amount were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0213] After spraying the coating solution, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 75±10°C. Drying can be performed within the range of residual solvent allowed by the pharmaceutical binder used, and can be performed by vacuum drying, oven drying, or the like.

[0214] Experimental Example 4. Evaluation of acid resistance In order to eliminate the influence of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and the dissolution evaluation of Examples 31, 32, 34, 37 and 38 was performed according to the United States Pharmacopeia (USP) Apparatus 1 (basket) to evaluate their acid resistance under acidic conditions.

[0215] The elution conditions were set as follows: pH 1.2 (HCl buffer solution); 37 ± 0.5 °C; medium 900 ml; rotation speed 100 rpm. The sample solution obtained after the start of elution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies). [Table 14]

[0216] As can be seen from Table 14 above, in the case of Examples 31, 32, 34, 37 and 38, which contain a delayed release regulating layer, it was confirmed that under acidic medium conditions, tegoprazan was not dissolved within 2 hours (120 minutes) or only a low dissolution rate was observed after 90 minutes, suggesting that acid resistance was sufficiently ensured.

[0217] Experimental Example 5. Evaluation of dissolution under weakly alkaline conditions After the acid resistance evaluation in Experimental Example 4 was completed, the dissolution property of the delayed release controlled pellets was evaluated in a weak alkaline medium.

[0218] Specifically, after the acid resistance evaluation was completed, the basket containing the pellets (apparatus 1) was placed in a preheated pH 6.8 (phosphate buffer); 37 ± 0.5 °C; 900 ml medium; and 100 rpm rotation speed, and the sample solution obtained after the start of the elution was analyzed using an ultraviolet spectrometer of a high performance liquid chromatography (HPLC; Agilent Technologies), and the results are shown in Table 15 below. [Table 15]

[0219] Experimental Example 6. Evaluation of the effect of pharmacokinetic absorption in beagle dogs In this disclosure, all experimental procedures related to the evaluation of pharmacokinetic properties in non-clinical models were performed in accordance with the Institutional Animal Care and Use Committee (IACUC) regulations and taking into account human equivalent doses (HEDs).

[0220] To evaluate the in vivo pharmacokinetic properties of the pellets (test groups) of Examples 12 to 14, the commercially available K-CABR tablet (control group 1) and Example 8 (control group 2) not containing a release-regulating layer were used as the control groups. Each pellet of the test group and control group 2 was filled into a hard capsule so as to contain the same dose of tegoprazan as the K-CABR tablet, and a non-clinical study was performed.

[0221] The non-clinical model animals used in the study were 15 beagle dogs (20±2 months old, male, average weight 13±2 kg) divided into 3 groups. Each test drug was orally administered in a single-dose parallel design in a fasting state after fasting for more than 12 hours on the day before administration.

[0222] Blood samples were collected from the cephalic vein using a disposable 3 ml syringe before administration (0 h) and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. 4 ml sodium heparin tubes containing anticoagulant (BD Biosciences, USA) were used as blood sample containers. The collected blood was centrifuged at 3,000 rpm for 15 min to separate plasma, which was then stored in a low-temperature (-70°C) freezer until analysis.

[0223] The analytical equipment used was a liquid chromatography mass spectrometer (LC-MS), and the analysis was performed in in-house method validation mode and electrospray ionization mode. The results are shown in Table 16 and Figure 2. [Table 16]

[0224] As shown in Table 16 and Figure 2 above, it was confirmed that Control Group 2 exhibited a faster Tmax and a higher Cmax value due to an increase in the surface area after the hard capsule membrane disintegrates or dissolves in the body, suggesting high in vivo exposure within a short period of time after administration, compared to Control Group 1. Furthermore, it was confirmed that Examples 12 to 14 exhibited different in vivo absorption rates due to the pH-dependent physical properties of the enteric coating used for release regulation, and that Examples 12 to 14, which included a delayed release regulating layer, exhibited a delayed Tmax value of the plasma concentration of tegoprazan, compared to the control group.

[0225] Experimental Example 7. Evaluation of the effect of the type of inert particles on pharmacokinetic absorption in minipigs To evaluate the effect of the type of inert particles on the in vivo pharmacokinetic absorption, each of the pellets of Examples 15, 17, 32 and 34 was filled into a hard capsule so as to contain the same amount of tegoprazan, and a non-clinical study was carried out.

[0226] As a non-clinical model, minipigs, which have a relatively long digestive tract compared to beagles, were selected and a comparative evaluation was performed using a single-dose parallel design.

[0227] Minipigs (8-11 month old males, average weight 25.9±1.4kg) were divided into groups of 3. Each test drug was orally administered in a single dose parallel design in the fasted state after fasting for 12 hours or more on the day before administration.

[0228] Approximately 3 ml of blood was collected from the jugular vein using a disposable syringe at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hours after administration. Heparinized tubes (5 IU / mL) were used as blood sample containers. The collected blood was centrifuged at 3,000 rpm for 5 minutes to separate plasma, which was then stored in a low-temperature (-70°C) freezer until analysis.

[0229] Plasma concentrations of the drugs were analyzed using LC-MS / MS in in-house method validation mode and electrospray ionization mode, and the results are shown in Table 17 below and FIG. [Table 17]

[0230] As shown in Table 17 and Figure 3, of the two types of inert particles used in the experiment, Examples 32 and 34, which used inert particles containing an organic acid, showed higher in vivo exposure of the release-modifying formulation containing tegoprazan.

[0231] Although there are some differences in the length of the intestine and the pH in the intestine depending on the animal species, the environment of the miniature pig is similar to that of the human. Therefore, the above results suggest that the in vivo absorption rate of tegoprazan can be increased when the pharmaceutical composition of the present disclosure is used with inert particles containing an organic acid.

[0232] Experimental Example 8. Evaluation of the effect of type of inert particles on pharmacokinetic absorption in monkeys Monkeys, which are the animal model most similar to humans in terms of anatomical, physiological, and endocrinological characteristics, were used as the animal model. Using this animal model, the effects of different types of inert particles on pharmacokinetic absorption were compared using a single-dose parallel design method.

[0233] In order to evaluate the effect on pharmacokinetic absorption in vivo, each of the pellets of Examples 15 and 32 was filled into a hard capsule so as to uniformly contain tegoprazan, and a non-clinical study was carried out.

[0234] The non-clinical model animals used in the study were cynomolgus monkeys (male, 30-50 months old, average weight 3.19±0.37kg), a total of six monkeys divided into three groups. Each test drug was orally administered in a single-dose parallel design in a fasting state after fasting for at least 16 hours on the day before administration.

[0235] Approximately 1 ml of blood was collected from the femoral vein using a disposable syringe at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after oral administration. BD MicrotainerR (heparin sodium tube, BD Biosciences, USA) was used as a blood sample container. The collected blood was centrifuged at 3,000 rpm and 4°C for 15 minutes to separate plasma, which was then stored in a low-temperature (-70°C) freezer until analysis.

[0236] Plasma concentrations of the drugs were analyzed using LC-MS / MS in in-house method validation mode and electrospray ionization mode, and the results are shown in Table 18 below and FIG. [Table 18]

[0237] As shown in Table 18 and FIG. 4, of the two types of inert particles used in the experiment, Example 32, which used inert particles containing an organic acid, showed a high in vivo exposure amount of the release-modifying formulation containing tegoprazan.

[0238] These results suggest that the in vivo absorption rate of tegoprazan can be improved by using inert particles containing an organic acid.

[0239] Experimental Example 9. Evaluation of the effect of pharmacokinetic absorption in monkeys using a single-dose parallel design A series of tests and analysis-related experimental items were conducted to evaluate the effect of pharmacokinetic absorption of immediate release pellets and modified release pellets in monkeys using a single-dose parallel design under the same conditions as in Experimental Example 7. Monkeys (mean weight: 4.48±0.56 kg; age 4±2 years) were divided into groups of 6 animals, and each drug was administered to each animal group. The results are shown in Table 19 below. [Table 19]

[0240] As shown in Table 19, it was confirmed that in Examples 20 and 21 containing a delayed release modifying layer, Tmax was delayed compared to Example 8 not containing a delayed release modifying layer, suggesting that the formulation containing a delayed release modifying layer exhibits a modified release pattern. In addition, it was confirmed that the delayed release modified formulations of Examples 20 and 21 were similar to the immediate release formulation of Example 8 in terms of the results of in vivo exposure of the drug, and that the area under the concentration-time curve (AUC) of the pharmacokinetics (PK) of tegoprazan according to the release pattern of the formulation was similar between the respective Examples.

[0241] Examples 39 to 46 For coating with an active ingredient layer containing tegoprazan, coating solutions having the pharmaceutical additive compositions shown in Table 20 below were prepared together with various binders (solvent: qs), and sucrose-based inactive pellets (product names: Suglet, Colorcon) were coated with each coating solution using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 20]

[0242] The contents in Table 20 are expressed as the amount (mg) of pellets filled per capsule.

[0243] The operating conditions of the fluidized bed pellet coater were inlet air temperature 75±10°C, exhaust flap pressure 0.7±0.3 bar, and coating solution spray pressure 1.5±0.7 bar. In the coating solution spraying process, the partition height and the coating solution supply rate were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0244] After spraying the coating solution, the pellets were fluidized by supplying air at 75±10°C in a fluidized bed pellet coater and dried for about 30 to 120 minutes. Drying can be performed within the range of residual solvent allowed by the binder used, and can be performed by vacuum drying, oven drying, etc.

[0245] Experimental Example 10. Evaluation of dissolution In order to eliminate the influence of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and the dissolution evaluation of Examples 39 to 44 was performed according to the United States Pharmacopeia (USP) Apparatus 1 (basket).

[0246] The elution conditions were set as follows: pH 4.0 (acetate buffer); 37 ± 0.5 °C; medium 900 mL; rotation speed 50 rpm. The sample solution obtained after the start of elution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies). The results are shown in Table 21 below. [Table 21]

[0247] As shown in Table 21 above, it can be seen that the release rate of tegoprazan can be adjusted depending on the type of polymer. Specifically, it can be seen that the release rate of the active ingredient decreases as the viscosity of the polymer used increases, with Example 43 (using 5.0 mg VA) showing the lowest release rate and Example 44 (using 10.0 mg polyethylene glycol) showing the highest release rate.

[0248] Examples 47 to 55 For coating with an active ingredient layer containing tegoprazan, a coating solution having the composition shown in Table 22 below was prepared using pharmaceutical additives and a solvent, and the inactive pellets were coated with each coating solution. Coating was performed under substantially the same conditions and by the same method as in Examples 39 to 46. [Table 22]

[0249] Experimental Example 11. Dissolution Evaluation The dissolution evaluation of Examples 47 to 55 was carried out under substantially the same conditions and by the same method as in Experimental Example 10. The results are shown in Table 23. [Table 23]

[0250] As shown in Table 23 above, it can be seen that the release rate of tegoprazan can be adjusted by the amount of talc, in particular, the batch of Example 55 (using an excessive amount of talc (22.5 mg)) has the lowest release rate, and the batch of Example 50 (using a small amount of talc (7.5 mg)) has the highest release rate.

[0251] Examples 56 and 61 In order to increase the stability of the active ingredient layer containing tegoprazan and the pellets containing the same, ensure efficient formation of the coating layer, and increase the abrasion resistance, coating solutions having the compositions shown in Table 24 below were prepared, and a certain amount or the entire amount of the outer surfaces of the processed products including Examples 39, 50, or 51 were coated with each coating solution using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 24]

[0252] The operating conditions of the fluidized bed pellet coater were: inlet air temperature 50±10°C, exhaust flap pressure 0.6±0.2 bar, coating solution spray pressure 1.5±0.6 bar. In the coating solution spraying process, the partition height and the coating solution supply rate were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0253] After spraying the coating solution, the pellets were fluidized by supplying air at 75±10°C in a fluidized bed pellet coater and cured for about 30 to 120 minutes. The drying process could also be performed by an oven drying method.

[0254] Experimental Example 12. Dissolution evaluation In order to eliminate the influence of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and the dissolution evaluation of Examples 39 and 56 to 59 was performed according to the United States Pharmacopeia (USP) Apparatus 1 (basket).

[0255] The elution conditions were set as follows: pH 6.8 (phosphate buffer); 37 ± 0.5 °C; medium 900 mL; rotation speed 100 rpm. The sample solution obtained after the start of elution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies), and the results are shown in Table 25 below. [Table 25]

[0256] As shown in Table 25 above, the release rate can be adjusted depending on the presence or absence of a coating layer and the composition of the coating layer. Specifically, it can be seen that the release rate of the active ingredient decreases as the amount of the coating layer increases.

[0257] Therefore, it can be confirmed that the pharmaceutical composition of the present disclosure can release tegoprazan continuously by adjusting the release rate of tegoprazan, and in particular, it can be confirmed that tegoprazan can be released continuously even in the intestinal environment.

[0258] Therefore, it can be seen that the pharmaceutical composition of the present disclosure can have a controlled release pattern in which tegoprazan is continuously released in the region from the gastric fluid environment to the intestinal environment.

[0259] Examples 62 to 69 Enteric coating solutions having the compositions shown in Table 26 below were prepared using pharma- ceutically acceptable excipients and solvents, and a certain amount or the entire amount of the processed products including Examples 56, 67, or 61 were coated with each enteric coating solution using a fluidized bed pellet coater (GPCG-1, bottom spray, Glatt, Germany). [Table 26]

[0260] The operating conditions of the fluidized bed pellet coater used for coating were: inlet air temperature 35 ± 10°C, exhaust flap pressure 0.7 ± 0.3 bar, coating solution spray pressure 1.5 ± 0.7 bar. In the coating solution spraying process, the partition height and the supply amount of coating solution were appropriately adjusted while observing the fluidity according to the pellet loading amount.

[0261] After spraying of the coating solution was completed, the pellets were dried for about 30 to 120 minutes in a fluidized bed pellet coater while fluidizing them by supplying air at 40±10°C. Note that drying could also be performed by vacuum drying or oven drying.

[0262] Experimental Example 13. Evaluation of dissolution The dissolution evaluation of Examples 62 to 69 was carried out under substantially the same conditions and by the same method as in Experimental Example 12. The results are shown in Table 27. [Table 27]

[0263] As shown in Table 27, in Examples 62 to 69 in which sustained release and delayed controlled release were applied, tegoprazan was released for 720 minutes or more under weakly alkaline medium conditions. In other words, it is understood that the pellets of the present disclosure can be used as delayed and controlled release pellets that release tegoprazan in the intestinal environment and continuously release tegoprazan.

[0264] Furthermore, as shown in Table 27, both the batch using an organic solvent and the batch using only purified water achieved similar release duration, indicating that either solution composition can be used.

[0265] Furthermore, when Examples 64 to 66 are compared with Examples 67 to 69, it is found that the total dissolution rate tends to decrease as the enteric coating rate in the pellet increases, and even when pellets have the same enteric coating rate, if there is a difference in the release rate of the active ingredient, the total dissolution rate will differ. Therefore, it is found that the final dissolution rate can be adjusted as desired by adjusting the release rate of the active ingredient or the composition of the enteric coating layer.

[0266] Therefore, it can be seen that the pharmaceutical composition of the present disclosure can be used as a modified release formulation that modifies the release of tegoprazan to have a desired release (dissolution) rate.

[0267] Examples 70 to 74 To provide sustained and modified release formulations, granules having the composition shown in Table 28 below were prepared by adding pharmaceutical excipients and compressed into sustained release tablets. [Table 28]

[0268] Specifically, tegoprazan was mixed with mannitol, microcrystalline cellulose, and croscarmellose sodium in the amounts shown in Table 28 above, and sieved. The sieved mixture was placed in a high-shear mixer (DIOSNA), and granulated while adding the prepared binding liquid.

[0269] The prepared granules were dried and then milled using a suitable sized screen. The milled granules were mixed with the extragranular excipients shown in Table 28 above in the amounts shown in Table 28. After the blending process was completed, the mixture was lubricated by adding sieved magnesium stearate. The lubricated material was compressed into tablets using a suitable punch, thereby preparing sustained release tablets.

[0270] Experimental Example 14. Evaluation of dissolution properties of sustained release tablets Dissolution evaluation was performed using United States Pharmacopeia (USP) Apparatus 2 (paddle) under the following conditions: pH 6.8 (phosphate buffer); 37 ± 0.5°C; 900 mL of medium; 50 rpm rotation speed. The sample solution obtained after the start of dissolution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies), and the results are shown in Table 29 below. [Table 29]

[0271] As shown in Table 29, it can be confirmed that the sustained-release tablets of Examples 72 to 74 slowly and sustainably release tegoprazan in a weakly alkaline environment. Furthermore, a comparison of Examples 72 to 74 shows that the release rate of tegoprazan can be adjusted depending on the proportion of the sustained-release agent.

[0272] Examples 75 and 76 Granules having the composition shown in Table 30 below were prepared by adding pharmaceutical additives and compressing them to prepare immediate release tablets. Granules and tablets were prepared under substantially the same conditions and by the same method as in Examples 70 to 74, except that the ingredients and contents shown in Table 30 below were used. [Table 30]

[0273] Example 77 Using pharmaceutical excipients, mixtures having the compositions shown in Table 31 below were prepared. [Table 31]

[0274] Specifically, tegoprazan was sieved together with mannitol, microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide in the amounts shown in Table 31 above, and then mixed. Sieved magnesium stearate was added to this mixture, and the mixture was subjected to a lubrication process to prepare a powdery mixture.

[0275] Example 78 The immediate release tablets shown in Table 32 below were prepared. [Table 32]

[0276] Granules and uncoated tablets were prepared under substantially the same conditions and in the same manner as in Examples 70 to 74, except that the ingredients and contents shown in Table 32 above were used. The prepared tablets were then coated with Opadry white, thereby preparing the final coated tablets.

[0277] Example 79 Enteric coated tablets shown in Table 33 below were prepared using pharmaceutical additives. [Table 33]

[0278] Uncoated tablets were prepared under substantially the same conditions and in the same manner as Examples 70-74, except that the ingredients and contents shown in Table 33 above were used. The prepared uncoated tablets were then subjected to a first coating, a second coating, and a third coating, successively, using a tablet coater (Labcoat, O'hara) with the ingredients and contents shown in Table 33 above.

[0279] Examples 80 to 83 In order to realize various release patterns by combining the Examples, formulations containing a tegoprazan immediate-release portion and a tegoprazan modified-release portion were prepared in the combinations shown in Table 34 below. [Table 34]

[0280] To confirm immediate release and delayed release in tablet form, immediate release tablets (Example 78) and enteric coated tablets (Example 79) were combined to prepare Example 80. The immediate release / enteric coated pellets of Example 81 were a single formulation obtained by filling a hard capsule with the granules of Example 76 (immediate release portion) and the enteric coated pellets of Example 21 (modified release portion). The immediate release / enteric coated sustained release pellets of Example 82 were a single formulation obtained by filling a hard capsule with the granules of Example 76 (immediate release portion) and the enteric coated sustained release pellets of Example 62 (modified release portion). The immediate release / sustained release tablets of Example 83 were coated tablets prepared by compressing the granules of Example 76 and the granules of Example 72 into a bilayer tablet, and coating the bilayer tablet with Opadry 85F.

[0281] Experimental Example 15. Evaluation of dissolution properties of pharmaceutical preparations The dissolution properties of the preparations of Examples 80 to 83 were evaluated. The dissolution evaluation was carried out using a buffer transition dissolution test, which can provide an environment similar to the in vivo environment.

[0282] Specifically, the drug release pattern was examined for 2 hours using 0.1N hydrochloric acid solution (pH approximately 1.1), and then a buffer was added to increase the acidity to pH 7.4. 0.5% polysorbate 80 was then added, and the release rate of tegoprazan was compared and evaluated.

[0283] The elution conditions were USP elution apparatus 2 (paddle) at 50 rpm, and the sample solution obtained after the start of elution was analyzed using an ultraviolet spectrometer of high performance liquid chromatography (HPLC; Agilent Technologies). [Table 35]

[0284] Referring to the results of the buffer solution migration dissolution test in Table 35 above, it can be seen that since all of the Examples contain an immediate release portion and a release-modifying portion, the active ingredient was released quickly in an acidic solution and completely in a weak alkaline solution.

[0285] Specifically, comparing Examples 80 to 83, it was confirmed that the immediate release / sustained release bilayer tablet of Example 83, which does not include the concept of enteric coating, achieved immediate release as well as sustained release under acidic solution conditions (within 2 hours). In addition, in the case of Examples 80, 81, and 82, which include the concept of enteric coating, it was confirmed that only the immediate release portion was released under acidic solution conditions, and when a buffer was added to change the pH to 6.8, the release of the remaining release-modifying portion proceeded. In particular, in the case of Example 82, it was confirmed that the release amount did not increase rapidly even when the pH was changed because a release-modifying layer coating was added between the active ingredient layer and the enteric coating layer.

[0286] Therefore, it can be confirmed that the formulation of the present disclosure can release tegoprazan for a certain period of time according to a desired release rate in a range from the gastric fluid environment to the intestinal environment.

[0287] Experimental Example 16. Evaluation of the effect of pharmacokinetic absorption in monkeys using a single-dose parallel design For in vivo evaluation, non-clinical evaluation of the formulation combinations of Examples 80-83 was conducted in groups of 5 monkeys using a single-dose parallel design.

[0288] The non-clinical model animals used in the study were six cynomolgus monkeys (male, aged 30-53 months, average body weight 3.19±0.37 kg). Each test drug was orally administered to the animals in a fasting state using a single-dose parallel design method after fasting for 16 hours or more on the day before administration (in the case of Example 80, the immediate release tablet and the enteric-coated tablet were administered simultaneously). Blood was collected from the femoral vein using a disposable syringe 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours later.

[0289] BD MicrotainerR (heparin sodium tubes, BD Biosciences, USA) were used as blood sample containers. The collected blood was centrifuged at 3,000 rpm and 4°C for 15 minutes to separate plasma, which was then stored in a low-temperature (-70°C) freezer until analysis. Drug concentrations in plasma were analyzed by LC-MS / MS in in-house method validation mode and electrospray ionization mode. [Table 36]

[0290] The test results in Table 36 above confirmed that the IR / DR, IR / DRSR and IR / SR formulations according to Examples 80 to 83 of the present disclosure have a Tmax delay effect without affecting the total absorption amount compared to K-CABR tablets or IR capsules.

[0291] Therefore, it can be seen that the preparation of the present invention can achieve various release rates controlled by not only the immediate release portion but also the delayed release portion in an actual in vivo environment. In addition, since the preparation of the present disclosure can continuously release tegoprazan not only in the gastric fluid environment but also in the intestinal environment, it can be seen that the blood concentration of the active ingredient can be maintained high for a long period of time after taking the preparation.

[0292] Examples 84 to 87 As shown in Table 37 below, capsule formulations were prepared containing both a tegoprazan immediate release portion and a tegoprazan modified release portion, which are dual modified release combinations of the above embodiments. [Table 37]

[0293] Examples 84-87 were single dosage forms prepared by dual-filling an immediate release portion (powder (mixture) of Example 77) and a modified release portion (pellets of Examples 62, 63, 66, and 68, respectively) into a single capsule.

[0294] Experimental Example 17. Evaluation of dissolution properties of composite capsule formulation The dissolution test of the capsule formulation was carried out by a buffer solution migration dissolution test.

[0295] Specifically, the drug release pattern was examined for 2 hours using 0.1N hydrochloric acid solution (pH approximately 1.1), and then a buffer was added to increase the acidity to pH 6.8. Then, 0.5% polysorbate 80 was added, and the release rate of tegoprazan was compared and evaluated.

[0296] The dissolution conditions were USP dissolution apparatus 2 (paddle), 50 The sample solution obtained after the start of elution was analyzed using an ultraviolet spectrophotometer of a high performance liquid chromatograph (HPLC; Agilent Technologies). The results are shown in Table 38 below. [Table 38]

[0297] Referring to the results of the buffer solution transfer dissolution test in Table 38 above, it can be seen that the immediate release portion of all Examples was completely dissolved within 1 hour in the acidic solution. In addition, when comparing the dissolution rates and compositions between Examples, it was confirmed that in Examples 84 to 87, no dissolution occurred from the release-modifying portion in the acidic solution, but dissolution occurred depending on the composition of each Example after pH adjustment (2 hours later).

[0298] Therefore, since the formulation of the present disclosure contains an immediate release portion and a modified release portion, it can achieve not only immediate release of tegoprazan, but also delayed and / or sustained release of tegoprazan, and can continuously release tegoprazan in areas ranging from the gastric fluid environment to the intestinal environment.

[0299] As described above, the pharmaceutical composition of the present disclosure can maintain the therapeutic effect for a long time by controlling the release of the active ingredient, thereby improving the patient's compliance with medication. Therefore, the composition can be effectively used for diseases that require the patient to take a drug for a long period of time or diseases that require the patient to maintain a certain level of the drug in the blood during the time when the patient cannot take the drug.

Claims

1. a core comprising tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient; and a release modifier-containing layer formed on the core, The release-modifying agent comprises at least one selected from the group consisting of a release-sustaining agent and an enteric agent; the enteric coating agent is at least one selected from the group consisting of ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, and polymers thereof; shellac; and acrylic acid, methacrylic acid, or esters thereof, or copolymers formed therefrom; A modified release pharmaceutical composition, wherein the release sustaining agent comprises one or more selected from the group consisting of polyvinyl alcohol, polyethylene oxide, methacrylic acid copolymers, hydroxypropyl methylcellulose, ethylcellulose, povidone, and talc.

2. Core Inert particles; and An active ingredient layer comprising an active ingredient disposed on the inert particles 2. The modified release pharmaceutical composition of claim 1, comprising:

3. 3. The modified release pharmaceutical composition of claim 2, wherein the inert particles comprise at least one selected from the group consisting of white sugar, lactose, starch, mannitol, sucrose, dextrin, and microcrystalline cellulose.

4. 10. The modified release pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises an organic acid.

5. 5. The modified release pharmaceutical composition of claim 4, wherein the organic acid is at least one selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid.

6. 3. The modified release pharmaceutical composition according to claim 2, wherein the inert particles and the active ingredient are contained in the core in a weight ratio of 5:1 to 1:

5.

7. 2. The modified release pharmaceutical composition according to claim 1, wherein the core is a core tablet prepared by compressing a mixture of granules containing the active ingredient and pharma- ceutically acceptable excipients.

8. 2. The modified release pharmaceutical composition of claim 1, wherein the core is a granule comprising a mixture containing the active ingredient and pharma- ceutically acceptable excipients.

9. 9. The modified release pharmaceutical composition of claim 8, wherein the enteric coating agent is any one or more selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid copolymer L, and methacrylic acid copolymer S.

10. 10. The modified release pharmaceutical composition of claim 9, wherein the enteric coating agent comprises methacrylic acid copolymer L and methacrylic acid copolymer S in a weight ratio of 1:3 to 1:0.

2.

11. 10. The modified release pharmaceutical composition of claim 9, wherein the enteric-coated agent comprises the methacrylic acid-ethyl acrylate copolymer and the methacrylic acid copolymer S in a weight ratio of 0.3:1 to 3:

1.

12. 2. The modified release pharmaceutical composition of claim 1, wherein the release modifier-containing layer is pH-dependently soluble at pH 5.5 or above.

13. 2. The modified release pharmaceutical composition according to claim 1, wherein the release modifier-containing layer is contained in an amount of 10 to 70% by weight based on the weight of the pharmaceutical composition.

14. 10. The modified release pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises at least one additional coating layer.

15. The modified release pharmaceutical composition of claim 1 , wherein the core comprises a release modifier.

16. The pharmaceutical composition comprises: A core comprising as an active ingredient tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a first release modifier; and a release modifier-containing layer formed on the core, the release modifier-containing layer comprising a second release modifier, 16. The modified release pharmaceutical composition of claim 15, wherein the first release modifier and the second release modifier each independently comprise at least one selected from the group consisting of a release sustaining agent and an enteric agent.

17. 17. The modified release pharmaceutical composition of claim 16, wherein the pharmaceutical composition further comprises an additional coating layer comprising a third release modifier between the core and the release modifier-containing layer comprising the second release modifier.

18. 20. The modified release pharmaceutical composition of claim 17, wherein the first release modifier and the third release modifier comprise a release sustaining agent and the second release modifier comprises an enteric agent.

19. The pharmaceutical composition comprises, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, The modified release pharmaceutical composition according to any one of claims 1 to 18, wherein the pharmaceutical composition is for co-administration with an immediate release pharmaceutical composition which immediately releases the active ingredient.

20. The modified release pharmaceutical composition according to any one of claims 1 to 19, which is for preventing or treating a disease mediated by acid pump antagonist activity.

21. The modified release pharmaceutical composition according to any one of claims 1 to 20, wherein the pharmaceutical composition is in the form of a tablet, pellet or granule.

22. A capsule filled with the pharmaceutical composition according to any one of claims 1 to 21.

23. A tablet comprising the pharmaceutical composition according to any one of claims 1 to 21.

24. The tablet is a granule containing, as an active ingredient, tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; 24. The tablet of claim 23, wherein the granules comprise a core comprising the active ingredient and a release sustaining agent.

25. A granule comprising tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient, wherein the granule comprises a core containing an active ingredient or a core containing an active ingredient and a release sustaining agent; and 24. The tablet of claim 23, comprising an enteric agent-containing layer disposed on the core.

26. A first pharmaceutical composition of modified release type according to any one of claims 1 to 21, comprising tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient; and A formulation comprising tegoprazan, an optical isomer thereof, a pharma- ceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient, and a second pharmaceutical composition which immediately releases the active ingredient.

27. The formulation according to claim 26, wherein the weight ratio of the active ingredient contained in the first pharmaceutical composition to the second pharmaceutical composition is from 5:1 to 1:5 (wt:wt).

28. 27. The formulation of claim 26, wherein the first pharmaceutical composition and the second pharmaceutical composition are present as separate particles.

29. 27. The formulation of claim 26, wherein the second pharmaceutical composition comprises inert particles and an active ingredient layer formed on the inert particles, the active ingredient layer comprising the active ingredient.

30. 27. The formulation of claim 26, wherein the formulation is a capsule or tablet comprising particles comprising the first pharmaceutical composition and particles comprising the second pharmaceutical composition.

31. The formulation is a capsule, 31. The formulation of claim 30, wherein the first pharmaceutical composition and the second pharmaceutical composition are each independently a powder, pellets, granules, or tablet.

32. The formulation is a tablet, 31. The formulation of claim 30, wherein the first pharmaceutical composition and the second pharmaceutical composition are each independently a powder, pellets, or granules.

33. The formulation, a first layer comprising a first pharmaceutical composition; and a second layer formed on the first layer and comprising a second pharmaceutical composition; 33. The formulation of claim 32, which is a multi-layer tablet comprising:

34. 1. A formulation in which the active ingredient of a first pharmaceutical composition and the active ingredient of a second pharmaceutical composition are contained within a single particle, wherein the first pharmaceutical composition is a core comprising an active ingredient or a core comprising an active ingredient and a release modifier; and an enteric-containing layer formed on and surrounding the core; and wherein the second pharmaceutical composition is 27. The formulation of claim 26, disposed on and surrounding the enteric-coated layer.

35. 1. A formulation in which the active ingredient of a first pharmaceutical composition and the active ingredient of a second pharmaceutical composition are contained within a single particle, wherein the first pharmaceutical composition comprises a core comprising an active ingredient; and a release modifier comprising at least one selected from the group consisting of a release modifier and an enteric agent; and wherein the second pharmaceutical composition is disposed on and surrounds the core.

27. The formulation of claim 26.

36. 36. The formulation of claim 34 or 35, wherein the particles are pellets, granules or tablets.

37. 37. The formulation of claim 36, wherein the formulation is a capsule filled with at least one selected from the group consisting of pellets, granules and tablets.

38. 37. The formulation of claim 36, wherein the formulation is a tablet prepared by compressing at least one selected from the group consisting of pellets and granules.

39. The preparation according to any one of claims 26 to 38, wherein the preparation is for preventing or treating a disease mediated by acid pump antagonist activity.

40. Use of a modified release pharmaceutical composition according to any one of claims 1 to 21 or a formulation according to any one of claims 26 to 39 in the manufacture of a medicament for the prevention or treatment of a disease mediated by acid pump antagonist activity.

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