Pharmaceutical composition for preventing or treating drug-related peptic ulcers containing zastaprazan or a pharmaceutically acceptable salt thereof

Abstract

The present invention discloses a pharmaceutical composition for preventing or treating drug-related peptic ulcers, comprising zastaprazan or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to the use of zastaprazan for the prevention, treatment, or prevention of recurrence of drug-related peptic ulcers. Specifically, the present invention relates to a pharmaceutical composition that can prevent and treat peptic ulcers induced by the administration of nonsteroidal anti-inflammatory drugs by suppressing or delaying the onset of the ulcers and suppressing their recurrence. [Background technology]

[0002] The sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) as the primary treatment for chronic diseases has increased dramatically in recent years. This has led to frequent reports of gastrointestinal side effects, such as gastrointestinal damage and bleeding, including peptic ulcers. While NSAIDs are believed to have a role in pain relief, their long-term use can make the stomach wall folds more vulnerable to ulcers and damage. Previous large-scale randomized controlled studies have reported that the incidence of symptomatic peptic ulcers in NSAID-using patients was 2.7–4.5%, and major complications, such as bleeding and perforation, were 1.0–1.5%.

[0003] Untreated peptic ulcers can lead to serious complications such as gastric or duodenal bleeding, perforation of the gastric or duodenal wall, penetration of the ulcer through the stomach or duodenum to other organs, and impaired motility of food moving from the stomach to the duodenum, as well as frequent recurrences.

[0004] In short, it is considered important to prevent and treat the onset of peptic ulcers associated with the administration of nonsteroidal anti-inflammatory drugs. Furthermore, there is currently a strong demand for a means to safely and effectively prevent the recurrence of peptic ulcers without side effects, even if nonsteroidal anti-inflammatory drugs are taken after the peptic ulcer has been treated. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Republic of Korea Patent No. 10-1777971 Summary of the Invention [Problem to be solved by the invention]

[0006] The inventors of the present invention have recognized the need for research and development efforts into pharmaceutical compositions that can safely and effectively prevent the onset and treatment of peptic ulcers and prevent their recurrence without side effects even when nonsteroidal anti-inflammatory drugs are taken for a long period of time. Therefore, an object of the present invention is to provide a pharmaceutical composition that uses zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for the safe, long-term, and effective prevention and treatment of peptic ulcers induced by the long-term administration of nonsteroidal anti-inflammatory drugs without side effects. [Means for solving the problem]

[0007] In order to achieve the above object, the present invention discloses the following means.

[0008] In one aspect, the present invention discloses a pharmaceutical composition for preventing, treating, or preventing the recurrence of peptic ulcer, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein the peptic ulcer is caused by administration of a nonsteroidal anti-inflammatory drug. [Effects of the Invention]

[0009] The present invention relates to a pharmaceutical composition for preventing, treating, or preventing recurrence of peptic ulcer, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. The pharmaceutical composition according to the present invention has the advantage of being able to prevent the onset of peptic ulcer, treat it, and prevent its recurrence, even when a nonsteroidal anti-inflammatory drug is administered repeatedly and continuously over a long period of time.

[0010] The present invention provides a pharmaceutical composition for the prevention, treatment, or prevention of recurrence of peptic ulcers, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. This has the advantage that co-administration of zastaprazan of the present invention with a nonsteroidal anti-inflammatory drug does not affect the pharmacokinetic (PK) properties of either drug, allowing each drug to exhibit sufficient efficacy. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows the results of measuring ulcer area when zastaprazan and esomeprazole were administered in combination in a naproxen-induced peptic ulcer model in a preclinical animal experiment. [Figure 2] 1 shows the mean plasma concentration-time profile of zastaprazan citrate when coadministered with aceclofenac to demonstrate whether the coadministration affects the pharmacokinetic (PK) profiles of both individual drugs. (Error bars in the figure indicate standard deviation.) [Figure 3] FIG. 1 shows the mean plasma concentration-time profile of aceclofenac when coadministered with zastaprazan to demonstrate whether this coadministration affects the pharmacokinetic (PK) profiles of both individual drugs (error bars in the figure indicate standard deviation). [Figure 4]FIG. 1 shows the mean plasma concentration-time profile of zastaprazan citrate when coadministered with meloxicam to demonstrate whether the coadministration affects the pharmacokinetic (PK) profiles of both individual drugs (error bars in the figure indicate standard deviation). [Figure 5] FIG. 1 shows the mean plasma concentration-time profile of meloxicam when coadministered with zastaprazan to demonstrate whether this coadministration affects the pharmacokinetic (PK) profiles of both individual drugs (error bars in the figure indicate standard deviation). [Figure 6] FIG. 1 shows the mean plasma concentration-time profile of zastaprazan citrate when co-administered with naproxen to demonstrate whether the co-administration affects the pharmacokinetic (PK) profiles of both individual drugs (error bars in the figure indicate standard deviation). [Figure 7] 1 shows the mean plasma concentration-time profile of naproxen when zastaprazan and naproxen are coadministered to demonstrate whether this coadministration affects the pharmacokinetic (PK) profiles of both individual drugs (error bars in the figure indicate standard deviation). [Figure 8] 1 is a schematic summary of the clinical trial method in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0012] This specification will be explained in more detail below.

[0013] This will be explained in detail as follows. The terms used in this specification have been selected as widely used as possible, taking into consideration the functions of the present invention. However, this may vary depending on the intentions of engineers in the field, legal precedents, the emergence of new technologies, etc. In certain cases, the applicant may arbitrarily select terms, and in such cases, their meanings will be described in detail in the section describing the invention. Therefore, the terms used in this specification should not be simply defined by their names, but should be defined in light of the meanings of the terms and the overall content of the present invention.

[0014] Furthermore, unless otherwise specified herein or clearly contradicted by the context, all terms used in this disclosure, including technical and scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. In addition, commonly used terms and dictionary-defined terms should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and should not be interpreted as an ideal meaning or an overly formal meaning unless clearly defined in this application.

[0015] Numerical ranges are inclusive of the numerical values ​​defined in the range. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitation were expressly written. Every numerical limitation given throughout this specification is intended to include every better numerical range within the broader numerical range, as if such narrower numerical limitations were expressly written.

[0016] Each description and embodiment disclosed in the present invention below can be applied to other descriptions and embodiments related thereto. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific descriptions described below.

[0017] As used in this disclosure, terms such as "comprises," "having," "including," and "comprising" should be construed as open-ended terms (i.e., meaning "including, but not limited to") that include the possibility of including other embodiments, unless the phrase or sentence in which the term appears clearly indicates otherwise.

[0018] As used herein, zastaprazan may refer to zastaprazan, its pharmaceutically acceptable salt, a hydrate or solvate thereof, or a mixture thereof. Accordingly, as used herein, a pharmaceutical composition containing zastaprazan may refer to a composition containing zastaprazan, its pharmaceutically acceptable salt, a hydrate or solvate thereof, or a mixture thereof.

[0019] The present invention will be described in detail below.

[0020] Pharmaceutical compositions containing zastaprazan

[0021] The present invention discloses a pharmaceutical composition comprising zastaprazan.

[0022] Specifically, the present invention provides a pharmaceutical composition for preventing, treating, or preventing the recurrence of peptic ulcers, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein the peptic ulcers are caused by the administration of nonsteroidal anti-inflammatory drugs.

[0023] The pharmaceutical composition of the present invention can prevent or treat peptic ulcers induced by taking nonsteroidal anti-inflammatory drugs safely and effectively over the long term without side effects in subjects who have been taking nonsteroidal anti-inflammatory drugs continuously for a long period of time, and can prevent recurrence of such ulcers.

[0024] With the increase in elderly patients suffering from chronic diseases such as musculoskeletal diseases and cardiovascular diseases, the number of patients taking nonsteroidal anti-inflammatory drugs for a long period of time is also increasing. However, nonsteroidal anti-inflammatory drugs inhibit the production of gastric mucosa, causing gastric acid secretion and damaging the stomach wall. Since nonsteroidal anti-inflammatory drugs are in tablet form, most of them dissolve in the gastrointestinal tract and begin to be absorbed, which may physically irritate the gastrointestinal mucosa at this time. Therefore, long-term use may induce peptic ulcers, and even if the peptic ulcer is treated, taking nonsteroidal anti-inflammatory drugs may easily cause the peptic ulcer to recur.

[0025] The inventors of the present invention have developed a pharmaceutical composition containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Such a pharmaceutical composition has the advantage of preventing peptic ulcers while preventing the recurrence of peptic ulcers caused by taking nonsteroidal anti-inflammatory drugs.

[0026] In the present invention, zastaprazan is an example of an imidazo[1,2-a]pyridine derivative, and its chemical name is azetidin-1-yl-[8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone.

[0027] In the present invention, zastaprazan is an active ingredient for the prevention, treatment or prevention of recurrence of peptic ulcer.

[0028] In the present invention, the term "active ingredient" refers to a substance or group of substances, including a main ingredient or an effective ingredient, that are expected to directly or indirectly exert the efficacy and effect of the pharmaceutical composition through their inherent pharmacological action.

[0029] Zastaprazan of the present invention may exist in the form of a pharmaceutically acceptable salt, and acid addition salts formed with a pharmaceutically acceptable free acid are useful as the salt. In the present invention, the term "pharmaceutically acceptable salt" refers to any and all organic or inorganic acid addition salts of zastaprazan that are relatively non-toxic to patients and have an innocuous effective concentration, and the side effects attributable to the salt do not reduce the beneficial efficacy of zastaprazan. The free acid may be an organic or inorganic acid. Examples of inorganic acids that may be used include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and stannic acid. Examples of organic acids that may be used include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid.

[0030] The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in zastaprazan, unless otherwise specified. For example, pharmaceutically acceptable salts include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, which can be prepared by salt preparation methods well known in the art.

[0031] Specifically, the pharmaceutically acceptable salt of zastaprazan may be, but is not limited to, zastaprazan citrate salt (azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt).

[0032] In the present invention, the term "hydrate" refers to a compound in which the active ingredient zastaprazan or a pharmaceutically acceptable salt thereof is bound to water by non-covalent intermolecular forces, and contains a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a molar ratio of about 0.25 to about 10 moles per mole of the active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 3 moles, or about 5 moles, etc.

[0033] In the present invention, the term "solvate" means a compound in which the active ingredient zastaprazan or a pharmaceutically acceptable salt thereof and a solvent are bound by non-covalent intermolecular forces, and which contains a stoichiometric or non-stoichiometric amount of the solvent. A suitable solvent is volatile, non-toxic, and can be administered to humans in extremely small amounts. Examples of the solvent include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-acetate, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, and heptane, but the solvate of the present invention is not limited to these examples. Specifically, the solvate may contain about 0.25 moles to about 10 moles of the solvent per mole of the active ingredient, and more specifically, the solvate may contain about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 3 moles, or about 5 moles, etc.

[0034] In the present invention, the term "peptic ulcer" refers to a gastrointestinal mucosal defect caused by the attack of gastric acid and pepsin. A peptic ulcer is defined as a lesion in the histologically decomposed mucosa extending below the mucosal layer. A peptic ulcer is an ulcer caused by an imbalance between defense factors that protect the mucosa and attacking factors that cause damage to the mucosa. Peptic ulcer is a term that collectively refers to gastric ulcer and duodenal ulcer, and is used synonymously with gastric ulcer and duodenal ulcer.

[0035] In the present invention, the term "subject" refers to a mammal, and specifically, mammals including humans include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice, and more specifically, may refer to a human. However, the subject may be a person who has developed or is at risk of developing a peptic ulcer due to continuous and / or long-term administration of a nonsteroidal anti-inflammatory drug, or a person who developed a peptic ulcer before administration of the pharmaceutical composition of the present invention and has since healed from the peptic ulcer.

[0036] In the present invention, the term "cured individual" refers to a mammal who has previously developed a peptic ulcer and who, after endoscopic examination, has been found to have no ulcer, bleeding, perforation of the stomach or duodenal wall, or the like, before administering the pharmaceutical composition of the present invention.

[0037] In the present invention, the subject is a person who has experienced at least one peptic ulcer but has since recovered due to continuous and / or long-term administration of a nonsteroidal anti-inflammatory drug before administering the pharmaceutical composition of the present invention. The onset or complete cure of a peptic ulcer in a subject can be determined by endoscopic examination. If endoscopic examination reveals bleeding, blood clots, or concentrated mucosal folds in the upper gastrointestinal tract (the stomach or duodenum), a peptic ulcer is considered to have developed. Specifically, if endoscopic examination of the upper gastrointestinal tract reveals an active ulcer (A1, A2) or healing ulcer (H1, H2) in the stomach or duodenum according to the Sakita-Miwa classification, a peptic ulcer is considered to have developed.

[0038] In the present invention, symptoms of peptic ulcer include heartburn, chest tightness, heavy stomach, pain in the pit of the stomach or in the stomach, sour burps (acid reflux), chest pain, and the like.

[0039] In the present invention, "preventing the recurrence of peptic ulcer" means preventing the recurrence of peptic ulcer by blocking or suppressing the onset of peptic ulcer at the source after the patient has experienced at least one peptic ulcer and has been cured. "Preventing peptic ulcer" means delaying the onset of peptic ulcer, and prevention can be considered complete if the onset of peptic ulcer is delayed for a predetermined period of time.

[0040] In the present invention, the nonsteroidal anti-inflammatory analgesic may be an acetic acid-derived nonselective nonsteroidal anti-inflammatory analgesic, an enolic acid-derived nonselective nonsteroidal anti-inflammatory analgesic, a fenamic acid-derived nonselective nonsteroidal anti-inflammatory analgesic, a p-aminophenol-derived nonselective nonsteroidal anti-inflammatory analgesic, a propionic acid-derived nonselective nonsteroidal anti-inflammatory analgesic, a salicylic acid-derived nonselective nonsteroidal anti-inflammatory analgesic, a selective COX-2 inhibitor, or a mixture thereof.

[0041] In the present invention, the acetic acid-derived non-selective nonsteroidal anti-inflammatory drug may be aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, zomepirac, or any combination thereof.

[0042] In the present invention, the enolic acid-derived nonsteroidal anti-inflammatory drug may be droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tenoxicam, or any combination thereof.

[0043] In the present invention, the fenamic acid-derived nonsteroidal anti-inflammatory analgesic may be flufenamic acid, mefenamic acid, meclofenamic acid, tolfenamic acid, or any combination thereof.

[0044] In the present invention, the nonsteroidal anti-inflammatory analgesic derived from p-aminophenol may be paracetamol, phenacetin, or any combination thereof.

[0045] In the present invention, the propionic acid-derived nonsteroidal anti-inflammatory drug may be alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, pharmaceutically acceptable forms of ketoprofen, loxoprofen, oxaprozin, pranoprofen, suprofen, or any combination thereof.

[0046] In the present invention, the salicylic acid-derived nonsteroidal anti-inflammatory analgesic may be acetylsalicylic acid, diflunisal, salsalate, or any combination thereof.

[0047] In the present invention, the selective COX-2 inhibitor may be celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, or any combination thereof.

[0048] In the present invention, the nonsteroidal anti-inflammatory analgesic may specifically include one or more selected from the group consisting of naproxen, aceclofenac, meloxicam, and celecoxib, but is not limited thereto.

[0049] In the present invention, the pharmaceutical composition can be administered once daily. Specifically, zastaprazan, its pharmaceutically acceptable salt, their hydrates or solvates, or a mixture thereof can be administered once daily for 2 weeks or more, or 4 weeks or more, and can be administered for 24 weeks or less, or 12 weeks or less. Specifically, the pharmaceutical composition can be administered once daily for 2 to 24 weeks, 4 to 24 weeks, 4 to 12 weeks, or 2 to 12 weeks.

[0050] In the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may contain 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg of zastaprazan (in the form of the free base), specifically, about 3.3, 6.6, 13.1, 26.2, or 52.4 mg of zastaprazan (in the form of the free base), and may contain 5 to 40 mg of zastaprazan citrate salt, specifically, 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg of zastaprazan citrate salt, more specifically, 10 mg, 20 mg, or 40 mg of zastaprazan citrate salt. As described above, the pharmaceutical composition of the present invention contains the above-mentioned low dose of zastaprazan, and when administered once daily, has the advantage of being able to effectively and safely prevent the recurrence of peptic ulcer or the onset of peptic ulcer caused by repeated administration of nonsteroidal anti-inflammatory drugs over a long period of time for a long period of time.

[0051] In the present invention, the subject may have an underlying disease such as a musculoskeletal and / or cardiovascular disease.

[0052] In the present invention, the pharmaceutical composition may contain one or more pharmaceutical additives including, but not limited to, an excipient, a disintegrant, a binder, and a lubricant.

[0053] In the present invention, the excipient may be one or more of microcrystalline cellulose, lactose hydrate, anhydrous lactose, sucrose, D-mannitol, starch, corn starch, and hard anhydrous silicic acid, but is not limited thereto.

[0054] In the present invention, examples of the disintegrant include starches or modified starches such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch; clays such as bentonite, montmorillonite, or veegum; celluloses such as hydroxypropyl cellulose or carboxymethyl cellulose; algins such as sodium alginate or alginic acid; cross-linked celluloses such as croscarmellose sodium; gums such as guar gum and xanthan gum; cross-linked polymers such as crospovidone; and anisotropic preparations such as sodium bicarbonate and citric acid. These may be used alone or in combination, and the disintegrant is not limited thereto.

[0055] In the present invention, the binder may be any one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silicon dioxide, mannitol, lactose, polyethylene glycol, and mixtures thereof, but is not limited thereto.

[0056] In the present invention, examples of the lubricant include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate, talc, etc. These may be used alone or in combination of two or more, and are not limited thereto.

[0057] In the present invention, the pharmaceutical composition may be a solid oral preparation, but is not limited thereto.

[0058] In the present invention, the solid oral preparation may be any one of tablets, film-coated tablets, capsules, powders, granules, pills, lozenges, oral jellies, and orally dissolving films, but is not limited thereto.

[0059] In particular, in the case of film-coated tablets, coating bases well known in the art can be used, and are not limited thereto.

[0060] For use in preventing the recurrence or development of peptic ulcers

[0061] The present invention provides use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for preventing peptic ulcers induced by administration of a nonsteroidal anti-inflammatory drug.

[0062] The present invention provides use of a pharmaceutical composition for preventing the recurrence of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0063] In the above-mentioned use of the present invention, the pharmaceutical composition may contain 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as zastaprazan (free base form), specifically, about 3.3, 6.6, 13.1, 26.2, or 52.4 mg of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as zastaprazan (free base form), and may contain 5 to 40 mg of zastaprazan citrate salt, specifically, 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg of zastaprazan citrate salt, more specifically, 10 mg, 20 mg, or 40 mg of zastaprazan citrate salt.

[0064] As described above, the pharmaceutical composition of the present invention contains the above-mentioned low dose of zastaprazan, and when administered once daily, has the advantage of being able to effectively and safely prevent the recurrence of peptic ulcer or the onset of peptic ulcer caused by repeated administration of nonsteroidal anti-inflammatory drugs over a long period of time for a long period of time.

[0065] In the use of the present invention for preventing the recurrence or onset of peptic ulcer, the pharmaceutical composition, subject, nonsteroidal anti-inflammatory drug, peptic ulcer, etc. are similarly applicable unless they contradict each other with the contents described above.

[0066] Use for the manufacture of a medicament for preventing the recurrence or onset of peptic ulcer

[0067] The present invention provides use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for the manufacture of a medicament for preventing peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug.

[0068] The present invention provides use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof for the manufacture of a medicament for preventing recurrence of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug.

[0069] The composition of the present invention for producing a medicament may be mixed with an acceptable carrier or the like, and may further contain other active ingredients.

[0070] In the use of the present invention for the manufacture of a medicament for preventing the recurrence or onset of peptic ulcer, the pharmaceutical composition, subject, peptic ulcer, etc. are similarly applicable unless they contradict each other as described above.

[0071] Methods for preventing recurrence or onset of peptic ulcer

[0072] The present invention provides a method for preventing the recurrence or onset of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug, by administering to a subject a pharmaceutically effective amount of a pharmaceutical composition containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0073] In the above method, the pharmaceutical composition of the present invention, the subject, the peptic ulcer, etc. are substantially the same as those described above, unless they are inconsistent with each other.

[0074] In the present invention, the term "pharmaceutically effective amount" refers to an amount effective for preventing the onset or recurrence of peptic ulcer, and includes, for example, an amount of a pharmaceutical composition administered to a subject that prevents the onset or recurrence of peptic ulcer, alleviates symptoms, inhibits direct or indirect pathological consequences, prevents metastasis, slows the rate of progression, alleviates or temporarily alleviates the condition, or improves prognosis. In other words, the pharmaceutically effective amount can be interpreted as including any dose of the composition that can prevent the onset and / or recurrence of peptic ulcer.

[0075] Specifically, in the method of the present invention for preventing the recurrence and / or onset of peptic ulcer, 5 mg to 100 mg of zastaprazan (in the form of the free base) can be administered to the subject once a day to prevent the recurrence and / or onset of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug. Specifically, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is administered to the subject once daily at a dose of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg of zastaprazan (free base), specifically, about 3.3, 6.6, 13.1, 26.2, or 52.4 mg of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (free base), or 5 to 40 mg of zastaprazan citrate salt, preferably 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg of zastaprazan citrate salt, more preferably 10 mg, 20 mg, or 40 mg of zastaprazan citrate salt, to effectively and safely prevent the recurrence or onset of peptic ulcer induced by repeated administration of continuous nonsteroidal anti-inflammatory drugs over a long period of time.

[0076] The method of the present invention for preventing the recurrence or onset of peptic ulcer has the advantage that by administering the pharmaceutical composition to a subject, the recurrence and / or onset of peptic ulcer induced by the administration of a nonsteroidal anti-inflammatory drug can be prevented safely and effectively over a long period of time without side effects, despite the continuous / long-term administration of the nonsteroidal anti-inflammatory drug.

[0077] The present invention will be described in more detail below with reference to Production Examples and Examples. These Production Examples and Examples are intended to more specifically explain the present invention, and the scope of the present invention is not limited by these Examples.

[0078] The active ingredient used in the following preparations and examples relates to zastaprazan citrate salt, which for convenience will be designated as zastaprazan or code name JP-1366.

[0079] Manufacturing example.

[0080] Production Example 1. Production of Zastaprazan Citrate Salt

[0081] Azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt was obtained according to the following steps. Specifically, azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was obtained according to the procedure described in Korean Patent Publication No. 10-1777971. The nuclear magnetic resonance (NMR) analysis results of the azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained above are as follows:

[0082] 1 H NMR (400 MHz, CDCl3); δ7.63(d, J=1.2 Hz, 1H), 7.13(dd, J =8.4, 6.8 Hz, 1H), 7.06-7.04(m, 2H), 6.42(d, J= 1.2 Hz, 1H), 4.86-4.84(m, 1H), 4.41-4.28(m, 4H), 4.37(d, J =4.4 Hz, 2H), 3.75-3.69(m, 1H), 2.43-2.34(m, 13H).

[0083] Next, the azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained above was mixed with an alcohol solvent (isopropyl alcohol; IPA), stirred, and then vacuum-dried at approximately 30°C to 35°C to obtain a dried product. Approximately 10 g of this was taken and stirred with approximately 167 g of acetone. A solution of approximately 5 g of citric acid in approximately 33 g of acetone was gradually added dropwise over 60 minutes and stirred at the same temperature for 1 hour. The mixture was cooled to approximately 20°C to 25°C and further stirred for 1 hour. The resulting solid was filtered, washed with acetone, and vacuum-dried to obtain azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt. The NMR analysis results of the azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt (zastaprazan citrate salt) obtained above are as follows.

[0084] 1 H NMR(400MHz, MeOD); δ 7.90(s, 1H), 7.06-7.15(m, 3H), 6.77(s, 1H), 4.50(t, J=7.2Hz, 2H), 4.45(s, 2H), 4.24(t, J=7.2Hz, 2H), 2.80(d, J=15.6Hz, 2H), 2.70(d, J=12.0, 2H), 2.39-2.44(m, 11H), 2.35(s, 3H)

[0085] Production Example 2: Production of JP-1366 Tablets 10 mg (Zastaprazan Citrate Salt 10 mg)

[0086] A mixture was obtained by mixing 10 mg of azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 136.5 mg of microcrystalline cellulose, 2.3 mg of sodium stearyl fumarate, 40.0 mg of anhydrous lactose, 6.0 mg of croscarmellose sodium, and 5.2 mg of magnesium stearate. The mixture was directly compressed to obtain tablets. Subsequently, the tablets were coated with 8.0 mg of Opadry® white to produce film-coated tablets.

[0087] The film-coated tablets produced in this manner are called "JP-1366 tablets 10 mg."

[0088] Production Example 3: Production of JP-1366 tablets 20 mg (zastaprazan citrate salt 20 mg)

[0089] A mixture was obtained by mixing 20 mg of azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 133.4 mg of microcrystalline cellulose, 6.4 mg of sodium stearyl fumarate, 40.0 mg of anhydrous lactose, 6.0 mg of croscarmellose sodium, and 4.2 mg of magnesium stearate. The mixture was directly compressed to obtain tablets. Subsequently, the tablets were coated with 8.0 mg of Opadry® 03B54445 pink to produce film-coated tablets.

[0090] The film-coated tablets produced in this manner are called "JP-1366 tablets 20 mg."

[0091] Manufacturing Example 4: Manufacturing of JP-1366 Capsules 20 mg (Zastaprazan Citrate Salt 20 mg)

[0092] A mixture was obtained by mixing 20 mg of azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 181.4 mg of dimannitol, 12.4 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate. The mixture was filled into hard capsules No. 1 using the capsule base to produce a capsule formulation.

[0093] The capsules thus produced are called "JP-1366 Capsules 20 mg."

[0094] Manufacturing Example 5: Zastaprazan 10mg placebo tablets (fake drug)

[0095] Except for not using the main ingredient, zastaprazan citrate, 10 mg zastaprazan placebo was prepared in the same manner as in Preparation Example 2. The film-coated tablets prepared in this manner are referred to as "JP-1366 tablets 10 mg placebo."

[0096] Preparation Example 6: Preparation of lansoprazole 15 mg formulation (control drug)

[0097] In the case of the lansoprazole preparation, Lanston Capsules 15 mg (Lansoprazole 15 mg) were purchased and used from Daiichi Pharmaceutical Co., Ltd. The purchased Lanston Capsules 15 mg are referred to as "Lansoprazole Capsules 15 mg."

[0098] Example 7: Lansoprazole 15mg placebo

[0099] Lansoprazole 15 mg placebo capsules were prepared in the same manner as Lanston capsules, except that the active ingredient, lansoprazole, was omitted and pharmaceutically acceptable excipients were added. The capsules prepared in this manner are referred to as "Lansoprazole Capsules 15 mg Placebo."

[0100] Example 1. Evaluation of the antiulcer activity of zastaprazan in an animal model of acute peptic ulcer induced by naproxen

[0101] To confirm the efficacy of zastaprazan in nonsteroidal anti-inflammatory drug-induced peptic ulcers, the antiulcer activity of zastaprazan was evaluated in a rat gastric injury model induced by naproxen, a nonsteroidal anti-inflammatory drug, and the antiulcer effect of zastaprazan was compared with that of esomeprazole.

[0102] 1. Test Animals

[0103] Species and strain: Male SD (Sprague-Dawley) rats

[0104] Reason for selecting the test system: SD rats used in this study are experimental animals suitable for efficacy evaluation tests, and were selected because a wealth of basic test data has been accumulated regarding gastrointestinal mucosal injury models, and it was thought that such data could be used to analyze and evaluate the test results.

[0105] Age at time of acquisition: Approximately 7 weeks old

[0106] Quarantine and acclimation: Approximately 7 days after acquisition (only healthy animals will be tested)

[0107] Identification: Individuals are identified using tail tagging and each enclosure is provided with an identification card recording the study number, study group, animal number and sex.

[0108] Age at time of test substance administration: Approximately 8 weeks old

[0109] Number of animals ordered: 12

[0110] Number of animals used: 12

[0111] 2. Rearing conditions

[0112] Breeding room: Clean animal room (Specific Pathogen Free; specific pathogen removal)

[0113] Ventilation frequency: Minimum 10 times / hour

[0114] Temperature and humidity range: 22±4℃, 50±20%(RH)

[0115] Lighting time and illuminance: 12 hours (lighting: 08:00~20:00, illuminance: 150~300 Lux)

[0116] Breeding box: Polysulfonate material breeding box

[0117] Number of animals per enclosure: 2

[0118] Rearing management: The bottom of the rearing box is covered with bedding straw (BETA CHIP (registered trademark), Northeastern Products, USA) that has been autoclaved (121°C, 20 minutes), and the feces and urine are treated and replaced twice a week.

[0119] Type and name of feed: Irradiated solid feed for rodents (PMI LabDiet® 5053, USA)

[0120] Feed supply: Ad libitum feeding using a feeder

[0121] Type of drinking water: Tap water sterilized with ultraviolet light and high-pressure steam after reverse osmosis treatment

[0122] Drinking water: Use 500 mL rat-specific water bottles, which should be changed once or twice a week. Wash and sterilize the water bottles before use. Use purified water and UV-sterilized water for drinking.

[0123] 3. Test Method

[0124] To induce gastric damage, experimental animals were orally administered naproxen at a dose of 40 mg / kg once a day for 5 days. The volume of the administered solution was 5 mL / kg. After 4 hours had passed since the last naproxen administration, the animals were anesthetized and the abdomen was opened to remove the stomach.

[0125] Specifically, non-fasted male SD rats were orally administered 40 mg / kg of naproxen once a day for 5 days, and the stomachs were removed 4 hours after the last naproxen administration.

[0126] Group composition and dosage setting: The composition of the test groups and the dosages administered are as follows:

[0127] [Table 1]

[0128] Administration site and method: The test substance (zastaprazan, JP-1366) and the control substance (esomeprazole) were orally administered in parallel with naproxen administration. The individual dose was calculated based on the body weight before administration and administered orally at a volume of 5 mL per kg of body weight. Administration of the test substance, control substance, and naproxen was performed 30 minutes apart.

[0129] Dosage frequency and duration: Once a day for 5 days (total of 5 times)

[0130] 4. Observation and inspection items

[0131] A. General symptom observation

[0132] Before and after administration of the test substance, observe each individual animal for general symptoms and the occurrence of mortal / near-mortal animals. Records will be kept only for animals showing specific symptoms (no records will be kept for normal animals).

[0133] B. Weight measurement

[0134] The body weight of each animal is measured at the time of arrival, grouping, and before administration of the test substance. Each measurement is carried out using the same scale to minimize errors.

[0135] C. Autopsy and measurement of the area of ​​gastric damage

[0136] After the test is completed, the stomach damage caused by the test substance is evaluated by the ulcer index. Four hours after the last naproxen administration, the animals are anesthetized and exsanguinated, and the stomach is then removed. The removed stomach is incised along the greater curvature, the contents are removed, it is washed thoroughly with saline, it is spread well with a cotton swab, and secured with a pin, and then a photograph is taken. The area of ​​the gastric damage site and the entire stomach is measured using an image program (Leica Application Suite V4), and the ulcer index (%) = damaged area (mm 2 ) / total area (mm 2 ) x 100.

[0137] D. Histopathological examination

[0138] The excised gastric tissue is fixed in 10% buffered neutral formalin. The fixed tissue is then trimmed to a uniform thickness, and after undergoing the usual tissue processing process, is embedded in paraffin to prepare 4-5 μm tissue sections, which are then stained with hematoxylin and eosin (HE staining), a standard staining method. Preparation of hematoxylin and eosin stained slides and histopathological examination are outsourced to an external institution.

[0139] 5. Statistical Processing

[0140] Experimental results were statistically analyzed using a commercial statistical processing program (IBM® SPSS Statistics version 25.0) using Mann-Whitney analysis.

[0141] 6.Results

[0142] Referring to Figure 1, the ulcer area in the group treated with the test substance zastaprazan (JP-1366) was rapidly reduced in the naproxen-induced peptic ulcer model, confirming that the test substance zastaprazan (JP-1366) exhibited excellent anti-ulcer activity.

[0143] It can also be confirmed that the antiulcer efficacy of the test substance, zastaprazan (JP-1366), is superior to that of the control substance, esomeprazole.

[0144] Therefore, it can be confirmed that the test substance, zastaprazan (JP-1366), can prevent peptic ulcers induced by nonsteroidal anti-inflammatory drugs.

[0145] Additionally, in Example 1, an experiment was conducted to examine the antiulcer effect of administering a nonsteroidal anti-inflammatory drug to a subject in a non-fasting state, similar to when the drug is actually administered to a human. This confirmed the efficacy of the drug in preventing peptic ulcers induced by the administration of a nonsteroidal anti-inflammatory drug in humans as well.

[0146] Example 2. Evaluation of pharmacokinetic (PK) interactions and safety of zastaprazan with aceclofenac, meloxicam, or naproxen

[0147] Zastaprazan is a potassium-competitive gastric acid secretion inhibitor that reversibly inhibits the H+,K+-adenosine triphosphatase and exhibits a faster onset of action than proton pump inhibitors. Zastaprazan can be used not only to treat gastrointestinal disorders caused by gastric acidity, but also to prevent gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs. To confirm this, the pharmacokinetic (PK) interactions and safety of zastaprazan with aceclofenac, meloxicam, and naproxen were evaluated in clinical trials in healthy subjects.

[0148] -PART 1: Pharmacokinetic (PK) interaction between Zastaprazan and Aceclofenac

[0149] -PART 2: Pharmacokinetic (PK) interaction between zastaprazan and meloxicam

[0150] -PART 3: Pharmacokinetic (PK) Interactions Between Zastaprazan and Naproxen

[0151] 1. Test drug

[0152] A. Test drug 1-zastaprazan 40mg

[0153] JP-1366 tablets 20mg x 2 capsules (zastaprazan citrate salt 40mg)

[0154] B. Test drug 2 - Aceclofenac 100mg

[0155] Airtal Tablets (Aceclofenac 100mg)

[0156] C. Test drug 3-meloxicam 15mg

[0157] Mobic® Capsules 15 mg (Meloxicam 15 mg)

[0158] D. Test drug 4-naproxen 500mg

[0159] Naxen (registered trademark) F Tablets (naproxen 500 mg)

[0160] 2. Test Method

[0161] <PART 1>

[0162] Subjects who volunteered for PART 1 were assigned a subject number on the day before the first administration of the investigational drug in Period 1 (-1d). They then received one tablet of aceclofenac on Day 1 of Period 1, two capsules of JP-1366 on Days 4-8 of Period 2, and two capsules of JP-1366 in combination with one tablet of aceclofenac on Day 9 of Period 3. Blood samples were taken from each subject at designated times to evaluate the pharmacokinetics of the investigational drug, and all subjects underwent safety evaluations according to a designated schedule.

[0163] After completing all clinical trials, subjects were given a post-trial visit within 14 to 20 days to choose from, including vital signs measurement, physical examination, confirmation of abnormal reactions, confirmation of prior / concomitant medications, clinical laboratory tests, and electrocardiograms.

[0164] <PART 2>

[0165] Subjects who volunteered for PART 2 were assigned a subject number on the day before the first administration of the investigational drug in Period 1 (-1d). They then received two capsules of JP-1366 from Days 1 to 5 of Period 1, one capsule of meloxicam from Days 15 to 19 of Period 2, and two capsules of JP-1366 in combination with one capsule of meloxicam from Days 22 to 26 of Period 3. Blood samples were taken from each subject at designated times to evaluate the pharmacokinetics of the investigational drug, and all subjects underwent safety evaluations according to a designated schedule.

[0166] After completing all clinical trials, subjects were selected to undergo a post-trial visit between 31 and 37 days, which included measurement of vital signs, physical examination, confirmation of abnormal reactions, confirmation of prior / concomitant medications, clinical laboratory tests, and electrocardiograms.

[0167] <PART 3>

[0168] Subjects who volunteered for PART 3 were assigned a subject number on the day before the first administration of the investigational drug in Period 1 (-1d). They then received two capsules of JP-1366 from Days 1 to 5 of Period 1, one naproxen tablet from Days 15 to 19 of Period 2, and two capsules of JP-1366 in combination with one naproxen tablet from Days 22 to 26 of Period 3. Blood samples were taken from each subject at designated times to evaluate the pharmacokinetics of the investigational drug, and all subjects underwent safety evaluations according to a designated schedule.

[0169] After completing all clinical trials, subjects were selected to undergo a post-trial visit between 31 and 37 days, which included measurement of vital signs, physical examination, confirmation of abnormal reactions, confirmation of prior / concomitant medications, clinical laboratory tests, and electrocardiograms.

[0170] 3. Pharmacodynamic (PK) analysis

[0171] Blood samples for evaluation of the pharmacokinetics of zastaprazan (JP-1366) were collected at scheduled times.

[0172] A. Part 1 - 22 subjects

[0173] (1) Aceclofenac 100 mg (A)

[0174] : 1d 0h (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12h post-dose

[0175] (2) Zastaprazan 40 mg (Z)

[0176] : 4d 0h, 6d 0h, 7d 0h, 8d 0h (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24h (9d 0h) post-dose

[0177] (3) Zastaprazan 40 mg and aceclofenac 100 mg (Z+A)

[0178] : 9d 0h (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24h (10d 0h) (post-dose)

[0179] Part 2 - 22 subjects

[0180] (1) Zastaprazan 40mg (Z)

[0181] : 1d 0h, 3d 0h, 4d 0h, 5d 0h (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24h (6d 0h) (post-dose), 15d 0h (pre-dose)

[0182] (2) Meloxicam 15 mg (M)

[0183] : 19d 0h (pre-dose), 1, 2, 3, 4, 5, 6, 8, 12, 24h (20d 0h) post-dose

[0184] (3) Zastaprazan 40 mg and meloxicam 15 mg (Z+M)

[0185] : 22d 0h, 24d 0h, 25d 0h, 26d 0h (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24h (27d 0h) post-dose

[0186] Part 3 - 22 subjects

[0187] (1) Zastaprazan 40mg (Z)

[0188] : 1d 0h, 3d 0h, 4d 0h, 5d 0h (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24h (6d 0h) post-dose, 15d 0h (pre-dose)

[0189] (2) Naproxen 500 mg (N)

[0190] : 19d 0h (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12h post-dose

[0191] (3) Zastaprazan 40 mg and naproxen 500 mg (Z+N)

[0192] : 22d 0h, 24d 0h, 25d 0h, 26d 0h (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24h (27d 0h) post-dose

[0193] 4.Results

[0194] A. See PART 1 - Table 1, Figures 2 and 3

[0195] Zastaprazan C vs. Z+A (zastaprazan 40 mg and aceclofenac 100 mg) max,SS and AUC T,SS The geometric mean ratios (GMR) [90% confidence intervals, CI] for α and β were 1.0868 (0.9554-1.2362) and 0.9490 (0.9096-0.9902), respectively.

[0196] Aceclofenac C of Z+A (zastaprazan 40 mg and aceclofenac 100 mg) versus A (aceclofenac 100 mg) max,SS and AUC T,SS The GMRs [90% CI] for α and β were 1.1895 (1.0429-1.3568) and 1.0295 (0.9803-1.0812), respectively.

[0197] [Table 2]

[0198] (Table 1 above shows the pharmacokinetic parameters of zastaprazan (Z) and aceclofenac (A), with data expressed as mean ± standard deviation.)

[0199] a. See PART 2 - Table 2 and Figures 4 and 5

[0200] Zastaprazan C vs. Z+M (zastaprazan 40 mg and meloxicam 15 mg) max,SS and AUC T,SS The GMRs [90% CI] for and were 1.0926 (0.9387-1.2717) and 1.3332 (1.1494-1.5463), respectively.

[0201] Meloxicam C of Z+M (zastaprazan 40 mg and meloxicam 15 mg) versus M (meloxicam 15 mg) max,SS and AUC T,SS The GMRs [90% CI] for and were 1.0756 (0.9916-1.1668) and 1.0477 (0.9976-1.1002), respectively.

[0202] [Table 3]

[0203] (Table 2 above shows the pharmacokinetic parameters of zastaprazan (Z) and meloxicam (M), with data expressed as mean ± standard deviation.)

[0204] C. PART 3 - See Table 3 and Figures 6 and 7

[0205] Zastaprazan C vs. Z+N (zastaprazan 40 mg and naproxen 500 mg) max,SS and AUC T,SS The GMRs [90% CI] for and were 0.9148 (0.7956-1.0518) and 1.1089 (0.9835-1.2503), respectively.

[0206] Naproxen C of Z+N (zastaprazan 40 mg and naproxen 500 mg) vs. N (naproxen 500 mg) max,SS and AUC T,SSThe GMRs [90% CI] for α and β were 1.0491 (1.0088-1.0910) and 1.0155 (0.9900-+1.0417), respectively.

[0207] [Table 4]

[0208] (Table 3 above shows the pharmacokinetic parameters of zastaprazan (Z) and naproxen (N), with data expressed as mean ± standard deviation.)

[0209] D. Summary

[0210] No clinically significant pharmacokinetic (PK) interactions were observed between zastaprazan and aceclofenac, meloxicam, or naproxen, without any safety issues.

[0211] Example 3. Evaluation of the efficacy and safety of zastaprazan administration for the prevention of nonsteroidal anti-inflammatory drug-induced peptic ulcers

[0212] 1. Selection of subjects

[0213] A multicenter, parallel-design, double-blind, randomized, active-controlled, non-inferiority clinical trial was designed to evaluate the efficacy and safety of zastaprazan in preventing gastric and duodenal ulcers in patients with nonsteroidal anti-inflammatory drug-induced peptic ulcers.

[0214] Selection criteria

[0215] Eligible applicants must meet all of the following criteria:

[0216] 1. Adult men and women aged 19 years or older as of the date of written consent

[0217] 2. Subjects who have been diagnosed with musculoskeletal diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis at the time of screening and require continuous administration of nonsteroidal anti-inflammatory drugs (aceclofenac, meloxicam, naproxen, celecoxib) for more than 24 weeks.

[0218] 3.Subjects who have one or more of the following risk factors for ulcer development at the time of screening:

[0219] 1) 60 years of age or older

[0220] 2) Subjects with a history of peptic ulcer documented on upper gastrointestinal endoscopy or subjects with ulcer scars documented on upper gastrointestinal endoscopy (performed within 10 days of randomization)

[0221] 3) Concomitant use of low-dose aspirin (aspirin <81mg-325mg / day) (However, patients with this risk factor must maintain low-dose aspirin administration during the clinical trial period.)

[0222] 4) Concomitant use of 10 mg / day or less of prednisone (or a corticosteroid equivalent to or less than this dose) (However, patients with this risk factor must maintain administration of corticosteroids at this dose throughout the clinical trial period.)

[0223] 4. Subjects who fully understand this clinical trial and have given their written consent to participate in the clinical trial.

[0224] Exclusion criteria

[0225] The recipient must not meet any of the following criteria:

[0226] 1. Those who cannot undergo endoscopic examination

[0227] 2. As a result of an endoscopic examination of the upper gastrointestinal tract at the time of screening, the stomach or duodenum is classified as a Sakita-Miwa *Those with active ulcers (A1, A2) or healing ulcers (H1, H2) due to

[0228] * Sakita / Miwa classification

[0229] 1) Active stage ulcer

[0230] (1) Active stage (A1): The white coating is thick and protrudes from the periphery in some areas. Small bleeding and blood clots are often present. There is severe inflammation, including redness, swelling, and erosion around the periphery, and the periphery is elevated and large.

[0231] (2) Active stage (A2): The protruding white fur disappears, and its borders become clearly defined. The surrounding inflammation also becomes significantly milder, and the swelling becomes slightly smaller. Concentrated mucosal folds appear. Even if there is evidence of regenerated epithelium, it is very minimal.

[0232] 2) Healing ulcer

[0233] (1) Healing stage (H1): The ulcer begins to become shallower, and the white plaque is clean, so the edges become smooth. The regenerated epithelium becomes clear, the surrounding ridges almost disappear, and the mucosal folds reach the edges of the white plaque and become concentrated.

[0234] (2) Healing stage (H2): The ulcer shrinks significantly. The white coating thins. The width of the regenerated epithelium widens.

[0235] 3) Scar stage ulcer

[0236] (1) Scarring stage (S1): Mucosal loss has disappeared, but redness of the regenerated epithelium remains. Small discolored spots are often seen in the center. Mucosal folds gently extend to the center.

[0237] (2) Scarring stage (S2): The redness disappears, the regenerated epithelium is thick, and it has almost the same color as the surrounding mucosa. The concentration of folds also disappears, and in some cases only the concentration of mucosa is visible.

[0238] 3. Medical history

[0239] 1) Subjects who have a history of malignant tumors within the past 5 years from the time of screening. However, subjects with a history of malignant tumors of the digestive system will be excluded regardless of the duration.

[0240] 2) Those who have warning symptoms suggesting a malignant disease of the gastrointestinal tract (pain when swallowing, severe difficulty in swallowing, bleeding, weight loss, anemia, bloody stool, etc.) (However, this does not include those who have negative results after confirming the presence or absence of malignant disease through endoscopic examination and esophageal biopsy.)

[0241] 3) Patients who have gastroesophageal varices, Barrett's esophagus (greater than 3 cm), esophageal dysplasia, esophageal stricture, ulcer stricture, or acute gastrointestinal bleeding as a result of screening upper gastrointestinal endoscopy.

[0242] 4) Subjects with a history of or a history of Zollinger-Ellison syndrome or other gastric acid secretion disorders

[0243] 5) Subjects with a history of or suspected of having inflammatory bowel disease (IBD), including pancreatitis, primary esophageal motility disorder, irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, and Behçet's colitis.

[0244] 6) Persons who have undergone or are scheduled to undergo gastrointestinal or esophageal surgery such as gastric acid suppression surgery, gastrectomy, or gastric mucosal resection (excluding appendectomy, cholecystectomy, and polypectomy).

[0245] 7) Those who tested positive for Helicobacter pylori (H. pylori) in a screening test

[0246] 8) Subjects with clinically significant diseases of the blood, liver, kidney, cardiovascular system, respiratory system, endocrine system, urinary system, neuropsychiatric system, immune system, or blood tumors.

[0247] 9) Subjects with a history of drug or alcohol abuse within one year of screening

[0248] 4. Clinical Laboratory Tests

[0249] 1) Those who meet any of the following criteria in the screening results:

[0250] [1] Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceeding twice the upper limit of normal (ULN)

[0251] [2] Total bilirubin level exceeds twice the upper limit of normal (ULN)

[0252] [3] Alkaline phosphatase (ALP) or gamma-glutamyl transpeptidase (γ-GTP) levels exceeding twice the upper limit of normal (ULN)

[0253] 2) Those who have been found to be positive in any one of the following tests: screening results, Human Immunodeficiency Virus (HIV) antigen / antibody test, Hepatitis B antigen (HBsAg), Hepatitis C antibody (Anti-hepatitis C Virus (Anti-HCV) test, or Venereal Disease Research Laboratory (VDRL) test results.

[0254] However, the following cases may be included:

[0255] 2-1) HBsAg positive individuals with HBV-DNA levels less than 100,000 IU / mL

[0256] 2-2) HCV-Ab positive individuals who are HCV-RNA negative

[0257] 3) Subjects who have clinically significant abnormalities (Clinically Significant; CS) in electrocardiograms at screening.

[0258] 5. Allergic and drug hypersensitivity reactions

[0259] 1) Persons known to have hypersensitivity reactions to the clinical trial drug and its components

[0260] 2) Subjects with a history of clinically significant allergic disease (excluding mild allergic rhinitis that does not require medication) or hypersensitivity reactions (asthma, acute rhinitis, nasal polyps, vasculo-neural swelling, urticaria, allergic reactions, etc.) to other drugs (non-steroidal anti-inflammatory drugs, aspirin, antibiotics, etc.).

[0261] 6. Contraindicated drugs and therapies

[0262] 1) Subjects who require continuous administration of corticosteroids, antiplatelet agents, or anticoagulants during this clinical trial (However, this is permitted in the following cases.)

[0263] [1] Patients who had been taking low-dose aspirin (81 mg to 325 mg per day) for the purpose of preventing cardiovascular disease before participating in this clinical trial

[0264] [2] Administration of prednisone 10 mg / day (or equivalent corticosteroid dose)

[0265] [3] Topical corticosteroids used to treat musculoskeletal disorders such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

[0266] 2) Individuals who are taking or need to take any of the contraindicated drugs specified in this clinical trial (However, individuals taking contraindicated drugs may participate in this clinical trial after a one-week washout period. However, individuals taking the following contraindicated drugs may participate in this clinical trial after the washout period has elapsed, depending on the half-life of the drug.)

[0267] Drugs with a half-life greater than 24 hours: 2 weeks

[0268] If the period corresponding to five half-lives exceeds two weeks: five washout half-lives of the drug

[0269] 7. Pregnant and nursing women or those with a positive pregnancy test result at screening

[0270] 8. Contraception

[0271] 1) Study subjects and their spouses (or partners) who do not use medically accepted contraception during the clinical trial. Methods that fall under "medically accepted contraception" are as follows:

[0272] [1] Use of an intrauterine device, which has a proven pregnancy failure rate

[0273] [2] Use of a double-blocking contraceptive method (male condom and occlusive cap, vaginal diaphragm or cervical cap for contraception) and simultaneous use of spermicide

[0274] [3] Infertility procedures (vasectomy, salpingectomy and ligation, hysterectomy)

[0275] 9. Subjects with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

[0276] 10. Subjects who have participated in other clinical trials within 4 weeks prior to participating in this clinical trial and have received or applied an investigational drug or medical device at least once.

[0277] 11. Subjects who are judged to be inappropriate for participation in this clinical trial according to the medical opinion of other investigators.

[0278] 2. Dosage, duration and method of administration

[0279] Depending on the treatment group to which they were randomly assigned, study subjects were to receive the assigned clinical trial drug orally at one tablet and one capsule once daily before a meal for 24 weeks, starting from the day after randomization, at a consistent time whenever possible.

[0280] [Table 5]

[0281] (In Table 4 above, ● represents JP-1366 tablets 10 mg, ○ represents JP-1366 tablets 10 mg placebo, ▲ represents lansoprazole 15 mg, and △ represents lansoprazole 15 mg placebo.)

[0282] Concomitant nonsteroidal anti-inflammatory drugs

[0283] Subjects will be administered one of the following non-steroidal anti-inflammatory drugs at the investigator's discretion from the date of randomization, and must maintain the same type and dose of the concomitant non-steroidal anti-inflammatory drug throughout the clinical trial.

[0284] 3. Clinical trial method

[0285] The study subjects will visit the clinical trial site at weeks 4, 12, and 24 from the date of randomization to undergo efficacy and safety evaluations according to the scheduled schedule. The efficacy evaluation will confirm the occurrence of peptic ulcers and gastrointestinal symptoms related to nonsteroidal anti-inflammatory drugs.

[0286] Safety evaluation will collect information on adverse events (AEs), vital signs (blood pressure, pulse, temperature), physical examination, and clinical laboratory tests (hematology tests, blood chemistry tests, urinalysis).

[0287] If a peptic ulcer is found by endoscopy during the clinical trial period, the patient will be terminated early from the clinical trial. If an ulcer is found and treatment is terminated early, this will be considered the end of treatment (EOT). A follow-up visit (F / U) will be conducted after the end of treatment (EOT).

[0288] 4. Efficacy evaluation variables

[0289] A. Primary efficacy evaluation variables:

[0290] Cumulative proportion of study subjects with peptic ulcer disease up to 24 weeks (%)

[0291] * Active stage / healing stage ulcers according to the Sakita-Miwa classification or newly discovered scarring stage ulcers in addition to scars found at the time of screening

[0292] A. Secondary efficacy evaluation variables:

[0293] Gastric or duodenal endoscopic bleeding up to 24 weeks ** Percentage of test subjects with

[0294] ** Those who fall under Class 1 or Class 2 of the Forest-Based Classification

[0295] C. Exploratory evaluation variables

[0296] 1. Percentage of study subjects who developed peptic ulcers by week 12 (%)

[0297] 2. Endoscopic bleeding of the stomach or duodenum up to week 12 ** Percentage of test subjects with

[0298] 3. Incidence (%) of peptic ulcers according to the type of nonsteroidal anti-inflammatory drug (aceclofenac, meloxicam, naproxen, celecoxib)

[0299] 4. The incidence rate of peptic ulcer according to risk factors for peptic ulcer

[0300] 5. The incidence of peptic ulcers according to the number of risk factors for peptic ulcer development

[0301] 6. Percent change in serum gastrin concentration compared to baseline

[0302] 7. The percentage of gastrointestinal symptoms measured by questionnaire at weeks 4, 12, and 24 compared to baseline

[0303] 8. Changes in blood hemoglobin (Hb) levels at weeks 4, 12, and 24 compared to baseline

[0304] 5. Safety Assessment Variables

[0305] Adverse events

[0306] -Vitality signs

[0307] -Physical examination

[0308] - Clinical laboratory test results

[0309] -Electrocardiogram

[0310] 6. Definition of analysis groups and statistical analysis methods

[0311] Analysis group definition

[0312] The analysis groups will be divided into three groups as shown below, and efficacy analysis will be performed based on the full analysis set (FAS) and the per protocol set (PPS), with the FAS being the primary analysis group. Safety analysis will be performed on the safety analysis set (Safety Set).

[0313] 1. Full Analysis Set (FAS)

[0314] This refers to a group of test subjects who received the investigational drug at least once in this clinical trial and underwent primary efficacy evaluation at least once.

[0315] 2. Per Protocol Set (PPS)

[0316] This refers to the set of all study subjects included in the FAS who have no serious protocol violations.

[0317] 3. Safety Analysis Set

[0318] In this clinical trial, it means a group of test subjects who receive the investigational drug one or more times.

[0319] Statistical analysis method

[0320] A. Primary efficacy evaluation variables

[0321] Cumulative percentage of study subjects with peptic ulcer disease by 24 weeks (%)

[0322] The proportion of study subjects who developed peptic ulcers from the time of drug administration to the 24th week compared to baseline will be presented for each treatment group. To compare whether there are differences between treatment groups, a chi-square test will be performed if the expected frequency is less than 5 in less than 20% of the cells, and a Fisher's exact test will be performed if the expected frequency is less than 5 in 20% or more of the cells.

[0323] Furthermore, logistic regression analysis will be used to confirm whether there are any differences between treatment groups when adjusting for the stratification factors of whether or not a peptic ulcer occurred at 24 weeks, the type of nonsteroidal anti-inflammatory drug (NSAID) the subject was taking (aceclofenac, meloxicam, naproxen, celecoxib), and the use of aspirin and / or prednisone (used / unused), which are risk factors for ulcer development.

[0324] B. Secondary efficacy evaluation variables

[0325] Percentage of study subjects with gastric or duodenal endoscopic bleeding by 24 weeks

[0326] : Compared to baseline, the proportion of study subjects who experienced gastric or duodenal endoscopic bleeding from the time of drug administration to Weeks 12 and 24 will be presented for each treatment group. To compare whether there are differences between treatment groups, a chi-square test will be performed if the expected frequency is less than 5 in less than 20% of the cells, and a Fisher's exact test will be performed if the expected frequency is less than 5 in 20% or more of the cells.

[0327] C. Exploratory evaluation variables

[0328] 1. Percentage of study subjects who developed peptic ulcers by week 12 (%)

[0329] The proportion of study subjects who developed peptic ulcers from the time of drug administration to the 12th week compared to baseline will be presented for each treatment group. To compare whether there are differences between treatment groups, a chi-square test will be performed if the expected frequency is less than 5 in less than 20% of the cells, and a Fisher's exact test will be performed if the expected frequency is less than 5 in 20% or more of the cells.

[0330] 2. Percentage of study subjects with gastric or duodenal endoscopic bleeding by week 12

[0331] : Compared to baseline, the proportion of study subjects who experienced gastric or duodenal endoscopic bleeding from the time of drug administration to Weeks 12 and 24 will be presented for each treatment group. To compare whether there are differences between treatment groups, a chi-square test will be performed if the expected frequency is less than 5 in less than 20% of the cells, and a Fisher's exact test will be performed if the expected frequency is less than 5 in 20% or more of the cells.

[0332] 3. Incidence (%) of peptic ulcers according to the type of nonsteroidal anti-inflammatory drug (aceclofenac, meloxicam, naproxen, celecoxib)

[0333] 4. The incidence rate (%) of peptic ulcer according to risk factors for peptic ulcer development

[0334] The incidence rate of peptic ulcers according to the risk factor items for ulcer development will be presented for each treatment group, and to compare whether there are any differences between treatment groups, a chi-square test will be performed if the number of cells with an expected frequency of less than 5 is less than 20% of the total, and a Fisher's exact test will be performed if the number of cells with an expected frequency of less than 5 is 20% or more of the total.

[0335] 5. The incidence rate (%) of peptic ulcer according to the number of risk factors for peptic ulcer

[0336] 6. Changes in gastrin levels at 4, 12, and 24 weeks compared to baseline

[0337] Descriptive statistics (mean, standard deviation, median, minimum, maximum) for gastrin values ​​at weeks 4, 12, and 24 and changes in gastrin values ​​from baseline to weeks 4, 12, and 24 after drug administration will be described. To compare differences between treatment groups, a two-sample t-test will be performed if the assumption of normality is met, and a Wilcoxon rank-sum test will be performed if the assumption of normality is not met. Additionally, if changes in each visit test value compared to baseline are not compared, a Wilcoxon signed-rank test will be used for analysis.

[0338] 7. The percentage of gastrointestinal symptoms measured by questionnaire at weeks 4, 12, and 24 compared to baseline

[0339] The proportion of study subjects who are free of NSAID-related gastrointestinal symptoms (such as acid reflux, upper abdominal pain or stomach upset, and indigestion) from the time of drug administration until 4, 12, and 24 weeks will be presented for each treatment group. To compare whether there are differences between treatment groups, a chi-square test will be performed if the number of cells with an expected frequency of less than 5 is less than 20% of the total, and a Fisher's exact test will be performed if the number of cells with an expected frequency of less than 5 is 20% or more of the total.

[0340] 8. Changes (%) in blood hemoglobin (Hb) levels at weeks 4, 12, and 24 compared to baseline

[0341] Descriptive statistics (mean, standard deviation, median, minimum, maximum) will be provided for blood hemoglobin values ​​at weeks 4, 12, and 24, and for the changes in hemoglobin values ​​from baseline to weeks 4, 12, and 24 after drug administration. To compare whether there are differences between treatment groups, a two-sample t-test will be performed if the assumption of normality is met, and a Wilcoxon rank-sum test will be performed if the assumption of normality is not met. In addition, if there are no changes in test values ​​at each visit compared to baseline, a Wilcoxon signed-rank test will be used for analysis.

[0342] * If the compliance rate is 80% or less, it is considered IP non-compliance.

[0343] D. Safety evaluation variables

[0344] 1. Abnormal reaction

[0345] The number, percentage, and 95% confidence interval of subjects with abnormal reactions, as well as the incidence rate, are presented for each treatment group. To compare whether there are differences between treatment groups, a chi-square test is performed when fewer than 20% of the cells have an expected frequency of less than 5, and a Fisher's exact test is performed when 20% or more of the cells have an expected frequency of less than 5.

[0346] The severity of the abnormal reaction, causality, measures taken for the clinical trial drug, treatment for adverse events, and their outcomes will be presented, along with the number of subjects with abnormal reactions, percentages and 95% confidence intervals, and the number of occurrences for each treatment group. To compare whether there are differences between treatment groups, a chi-square test will be performed if the number of cells with an expected frequency of less than 5 is 20% or less, and a Fisher's exact test will be performed if the number of cells with an expected frequency of less than 5 is more than 20%.

[0347] 2. Vitality signs, physical examination, clinical laboratory tests

[0348] For continuous data, descriptive statistics (mean, standard deviation, median, minimum, maximum) will be provided for each visit, and to compare differences between treatment groups, a two-sample t-test will be performed if the assumption of normality is met, or a Wilcoxon rank-sum test will be performed if the assumption of normality is not met. Additionally, if no comparison is made between visit changes in test values ​​compared to baseline, a Wilcoxon signed-rank test will be used.

[0349] For categorical data, frequencies and proportions are described for each visit, and to compare differences between treatment groups, a chi-square test is performed if the number of cells with an expected frequency of less than 5 is less than 20% of the total, and a Fisher's exact test is performed if the number of cells with an expected frequency of less than 5 is 20% or more of the total. The values ​​at baseline and each visit are divided into normal / abnormal categories, and a McNemar test is used to test whether the normal / abnormal proportions have changed before and after administration of the clinical trial drug.

[0350] Although specific portions of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing, treating, or preventing recurrence of peptic ulcer, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, The pharmaceutical composition, wherein the peptic ulcer is caused by administration of nonsteroidal anti-inflammatory drugs (NSAIDs).

2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of zastaprazan is zastaprazan citrate salt.

3. The pharmaceutical composition according to claim 1, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in an amount of 1 mg to 100 mg as zastaprazan.

4. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 5 to 40 mg of zastaprazan citrate salt.

5. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 10 mg of zastaprazan citrate salt.

6. The pharmaceutical composition according to claim 1, wherein the subject to which the pharmaceutical composition is administered is a subject who has experienced peptic ulcer caused by administration of a nonsteroidal anti-inflammatory drug.

7. The pharmaceutical composition according to claim 1, wherein the subject to which the pharmaceutical composition is administered is a subject who has experienced healing of a peptic ulcer.

8. 2. The pharmaceutical composition according to claim 1, wherein the nonsteroidal anti-inflammatory drug is an acetic acid-derived nonselective nonsteroidal anti-inflammatory drug, an enolic acid-derived nonselective nonsteroidal anti-inflammatory drug, a fenamic acid-derived nonselective nonsteroidal anti-inflammatory drug, a p-aminophenol-derived nonselective nonsteroidal anti-inflammatory drug, a propionic acid-derived nonselective nonsteroidal anti-inflammatory drug, a salicylic acid-derived nonselective nonsteroidal anti-inflammatory drug, a selective COX-2 inhibitor, or a mixture thereof.

9. The acetic acid-derived non-selective nonsteroidal anti-inflammatory analgesics include aceclofenac, acemetacin, actarit, alfenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, metiazinic acid, and the like. acid), Mofezolac, Nabumetone, Naproxen, Oxametacin, Sulindac, Zomepirac or any combination thereof; The enolic acid-derived nonsteroidal anti-inflammatory drug is droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tenoxicam, or any combination thereof; The fenamic acid-derived nonsteroidal anti-inflammatory analgesic drug may be flufenamic acid, mefenamic acid, meclofenamic acid, tolfenamic acid, or any combination thereof; The p-aminophenol-derived nonsteroidal anti-inflammatory analgesic drug may be paracetamol, phenacetin, or any combination thereof; The propionic acid-derived nonsteroidal anti-inflammatory drug may be alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, pharmaceutically acceptable forms of ketoprofen, loxoprofen, oxaprozin, pranoprofen, suprofen, or any combination thereof; The salicylic acid-derived nonsteroidal anti-inflammatory drug is acetylsalicylic acid, diflunisal, salsalate, or any combination thereof; or The selective COX-2 inhibitor is celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, or any combination thereof; The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is any one or more of the following:

10. 2. The pharmaceutical composition according to claim 1, wherein the nonsteroidal anti-inflammatory drug is one or more selected from the group consisting of naproxen, aceclofenac, meloxicam, and celecoxib.

11. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered once daily.

12. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated into a solid oral dosage form.

13. Use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for preventing peptic ulcers induced by administration of a nonsteroidal anti-inflammatory drug.

14. Use of a pharmaceutical composition for preventing recurrence of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

15. Use of a composition containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for the manufacture of a medicament for preventing peptic ulcers induced by administration of a nonsteroidal anti-inflammatory drug.

16. Use of a composition containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for the manufacture of a medicament for preventing recurrence of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug.

17. A method for preventing the recurrence or onset of peptic ulcer induced by administration of a nonsteroidal anti-inflammatory drug, comprising administering to a subject a pharmaceutically effective amount of a pharmaceutical composition containing zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

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