Pharmaceutical composition for prevention or treatment of drug-related peptic ulcer comprising zastaprazan or pharmaceutically acceptable salt thereof

Abstract

Disclosed in the present invention is a pharmaceutical composition for the prevention or treatment of drug-related peptic ulcer, comprising zastaprazan or a pharmaceutically acceptable salt thereof.

Description

Pharmaceutical composition for preventing or treating drug-associated peptic ulcer comprising zastaprazan or a pharmaceutically acceptable salt thereof

[0001] The present invention relates to the use of zastaprazan for the prevention, treatment, or recurrence prevention of drug-associated peptic ulcers. Specifically, the invention relates to a pharmaceutical composition capable of preventing and treating peptic ulcers induced by administration of NSAIDs by inhibiting or delaying their onset and suppressing their recurrence.

[0002] With the increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs) as primary treatment for chronic diseases, gastrointestinal side effects such as peptic ulcers and bleeding are frequently observed in clinical settings. This is because, while NSAIDs play a role in relieving pain, long-term use can make the stomach wall folds more susceptible to ulcers and damage. Previous large-scale randomized controlled trials reported that the incidence of symptomatic peptic ulcers in NSAID users was 2.7-4.5%, and major complications such as bleeding or perforation were 1.0-1.5%.

[0003] If peptic ulcers are left untreated, they can lead to serious complications such as bleeding in the stomach or duodenum, perforation of the stomach or duodenal wall, penetration of the ulcer into other organs through the stomach or duodenum, and obstruction of food movement from the stomach to the duodenum, or frequent recurrence.

[0004] Ultimately, it is important to prevent and treat the development of peptic ulcers caused by taking NSAIDs, and furthermore, there is an urgent need for a means to safely and effectively prevent the recurrence of peptic ulcers without side effects even when taking NSAIDs after peptic ulcers have been treated.

[0005] [Prior Art Literature]

[0006] [Patent Document]

[0007] (Patent Document 1) Korean Patent No. 10-1777971

[0008] The inventors of the present invention have identified the need for research and development of a pharmaceutical composition that can safely and effectively prevent the occurrence of peptic ulcers, treat them, and further prevent their recurrence without side effects, even with long-term use of NSAIDs. Accordingly, the present invention aims to provide a pharmaceutical composition that uses zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof to safely, long-term, and effectively prevent, treat, and prevent recurrence of peptic ulcers caused by long-term use of NSAIDs without side effects.

[0009] In order to achieve the above purpose, the present invention discloses the following means.

[0010] In one aspect, the present invention discloses 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, wherein the peptic ulcer is caused by administration of NSAIDs.

[0011] The present invention relates to a pharmaceutical composition for preventing, treating or preventing recurrence of peptic ulcers, 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 preventing the onset of peptic ulcers, treating them and preventing recurrence thereof even with long-term, repeated administration of NSAIDs.

[0012] The present invention provides a pharmaceutical composition for preventing, treating or preventing recurrence of peptic ulcers, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein co-administration of NSAIDs and zastaprazan of the present invention does not affect the pharmacokinetic (PK) characteristics of each drug, and thus each drug can exhibit sufficient efficacy.

[0013] Figure 1 shows the results of measuring the ulcer area when zastaprazan and esomeprazole were co-administered in a naproxen-induced peptic ulcer model in a preclinical animal experiment.

[0014] Figures 2 and 3 illustrate whether co-administration of zastaprazan and aceclofenac affects the PK profiles of each individual drug. They show the mean plasma concentration-time profiles of zastaprazan citrate (Figure 2) and aceclofenac (Figure 3). (In Figures 2 and 3, error bars represent standard deviations.)

[0015] Figures 4 and 5 show the mean plasma concentration-time profiles of zastaprazan citrate (Figure 4) and meloxicam (Figure 5) to demonstrate whether co-administration of zastaprazan and meloxicam affects the PK profiles of the two individual drugs. (In Figures 4 and 5, error bars represent standard deviations.)

[0016] [Revised 25.01.2024 under Article 91 of the Rules] Figures 6 and 7 show whether co-administration of zastaprazan and naproxen affects the PK profiles of the two individual drugs, and show the mean plasma concentration-time profiles of zastaprazan citrate (Figure 6) and naproxen (Figure 7). (In Figures 6 and 7, error bars represent standard deviations.) Figure 8 outlines the clinical trial method in Example 3.

[0017] Hereinafter, the present specification will be described in more detail.

[0018] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0019] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0020] Numerical ranges are inclusive of the values ​​defined in the ranges above. Any maximum numerical limitation given throughout this specification includes any lower numerical limitation, as if that lower numerical limitation were explicitly stated. Any minimum numerical limitation given throughout this specification includes any higher numerical limitation, as if that higher numerical limitation were explicitly stated. Any numerical limitation given throughout this specification will include any better numerical range within the broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0021] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0022] Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0023] As used herein, "zastaprazan" may refer to zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Accordingly, as used herein, a pharmaceutical composition comprising zastaprazan may refer to a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0024] Hereinafter, the present invention will be described in detail.

[0025] Pharmaceutical composition comprising zastaprazan

[0026] The present invention discloses a pharmaceutical composition comprising zastaprazan.

[0027] Specifically, the present invention provides 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, wherein the peptic ulcer is caused by administration of NSAIDs.

[0028] The pharmaceutical composition of the present invention can prevent or treat peptic ulcers caused by NSAIDs in a safe, long-term, and effective manner without side effects in a subject who continuously takes NSAIDs for a long period of time, and can prevent recurrence.

[0029] As the number of elderly patients suffering from chronic diseases such as musculoskeletal and cardiovascular diseases increases, the number of people taking NSAIDs for long periods of time is also increasing. However, NSAIDs damage the stomach lining by suppressing gastric mucosal production and stimulating gastric acid secretion. Furthermore, because NSAIDs are in tablet form, most dissolve in the stomach and begin to be absorbed. This physical irritation to the gastric mucosa can lead to peptic ulcers with long-term use. Even after a peptic ulcer has healed, NSAID use can easily lead to a recurrence of the disease.

[0030] The inventors of the present invention have developed a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. This pharmaceutical composition has the advantage of preventing peptic ulcers while also preventing the recurrence of peptic ulcers caused by NSAIDs.

[0031] 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.

[0032] In the present invention, zastaprazan is an active ingredient for preventing, treating or preventing recurrence of peptic ulcer.

[0033] In the present invention, “active ingredient” means a substance or group of substances that are expected to directly or indirectly exhibit the efficacy and effect of the pharmaceutical composition through inherent pharmacological action, and includes a main ingredient or effective ingredient.

[0034] The zastaprazan of the present invention may exist in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as a salt. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic acid addition salt of zastaprazan at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects caused by the salt do not diminish the beneficial effects of zastaprazan. Organic acids and inorganic acids can be used as free acids, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, or tartaric acid can be used as inorganic acids, and organic acids such as 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, carbonic acid, vanillic acid, or hydroiodic acid can be used.

[0035] Pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in zastaprazan, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl 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, and may be prepared by methods known in the art for preparing salts.

[0036] Specifically, a 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).

[0037] The term "hydrate" in the present invention means a hydrate in which the active ingredient, zastaprazan or a pharmaceutically acceptable salt thereof, and water are bound by non-covalent intermolecular forces, and which contains a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, etc.

[0038] The term "solvate" in the present invention refers to a composition in which the active ingredient, zastaprazan or a pharmaceutically acceptable salt thereof, is bound to a solvent by non-covalent intermolecular forces, and includes a stoichiometric or non-stoichiometric amount of the solvent. Preferred solvents are volatile, non-toxic, and can be administered to humans in extremely small amounts. For example, there are 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, heptane, etc., but the solvate of the present invention is not limited to these examples, and specifically, the solvate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, etc.

[0039] The term "peptic ulcer" in the present invention refers to a defect in the gastric mucosa caused by an attack by gastric acid and pepsin. When a histologically necrotic mucosa defect extends below the mucosal layer, it is called a peptic ulcer. A peptic ulcer refers to an ulcer caused by an imbalance between the defensive factors that protect the mucosa and the aggressive factors that cause mucosal damage. Peptic ulcer is a general term for gastric ulcer and duodenal ulcer, and is used synonymously with gastric and duodenal ulcer.

[0040] In the present invention, the term "subject" means 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 mean humans. The subject may be a person who has developed a peptic ulcer or is at risk of developing one due to continuous and / or long-term use of NSAIDs, or a person who has developed a peptic ulcer before administering the pharmaceutical composition according to the present invention and has subsequently healed the peptic ulcer.

[0041] In the present invention, the term “cured subject” refers to a mammal, and refers to a subject who has been confirmed by endoscopic examination to have no ulcer, bleeding, perforation of the stomach or duodenal wall, etc., prior to administration of the pharmaceutical composition according to the present invention after having developed peptic ulcer in the past.

[0042] In the present invention, the subject is a person who has experienced peptic ulcer at least once due to continuous and / or long-term use of NSAIDs before administering the pharmaceutical composition of the present invention, but has been cured, and the onset or complete cure of the peptic ulcer of the subject can be determined through an endoscopic examination. At this time, if bleeding or blood clots, or concentration of mucosal folds are confirmed in the upper gastrointestinal tract, such as the stomach or duodenum, through an endoscopic examination, a peptic ulcer can be considered to have occurred. Specifically, if the upper gastrointestinal tract endoscopic examination results in the stomach or duodenum as an active ulcer (A1, A2) or a healing ulcer (H1, H2) according to the Sakita-Miwa classification, it can be considered that a peptic ulcer has occurred.

[0043] In the present invention, symptoms of peptic ulcer may include heartburn, stuffiness, heartburn, belching, chest pain, etc.

[0044] In the present invention, “preventing recurrence of peptic ulcer” means preventing recurrence of peptic ulcer by fundamentally blocking or suppressing the onset of peptic ulcer after having experienced peptic ulcer at least once and then healed, and “preventing peptic ulcer” means delaying the onset of peptic ulcer. If the onset of peptic ulcer is delayed for a predetermined period of time, prevention can be considered complete.

[0045] In the present invention, the NSAIDs may be acetic acid-derived non-selective NSAIDs, enolic acid-derived non-selective NSAIDs, phenamic acid-derived non-selective NSAIDs, p-amino phenol-derived non-selective NSAIDs, propionic acid-derived non-selective NSAIDs, salicylic acid-derived non-selective NSAIDs, selective COX-2 inhibitors, or mixtures thereof.

[0046] In the present invention, the acetic acid-derived non-selective NSAIDs 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.

[0047] In the present invention, the enolic acid-derived NSAIDs may be Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, Tenoxicam, or any combination thereof.

[0048] In the present invention, the fenamic acid-derived NSAIDs may be flufenamic acid, mefenamic acid, meclofenamic acid, tolfenamic acid, or any combination thereof.

[0049] In the present invention, the p-aminophenol derived NSAIDs may be paracetamol, phenacetin or any combination thereof.

[0050] In the present invention, the propionic acid-derived NSAIDs may be Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen in a pharmaceutically acceptable form, Loxoprofen, Oxaprozin, Pranoprofen, Suprofen, or any combination thereof.

[0051] In the present invention, the salicylic acid-derived NSAIDs may be acetylsalicylic acid, diflunisal, salsalate, or any combination thereof.

[0052] In the present invention, the selective COX-2 inhibitor may be celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, or any combination thereof.

[0053] In the present invention, the NSAIDs may specifically include one or more selected from the group consisting of naproxen, aceclofenac, meloxicam, and celecoxib, but are not limited thereto.

[0054] In the present invention, the pharmaceutical composition may be administered once daily. Specifically, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be administered once daily for at least 2 weeks, or at least 4 weeks, and may be administered for up to 24 weeks, or up to 12 weeks. Specifically, the pharmaceutical composition may be administered once daily for 2 to 24 weeks, 4 to 24 weeks, 4 to 12 weeks, or 2 to 12 weeks.

[0055] In the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be contained in an amount of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg as zastaprazan (in the form of a free base), specifically about 3.3, 6.6, 13.1, 26.2, or 52.4 mg as zastaprazan (in the form of a free base), and may be contained in an amount of 5 to 40 mg as zastaprazan citrate salt, specifically about 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg as zastaprazan citrate salt, and more specifically about 10 mg, 20 mg, or 40 mg as zastaprazan citrate salt. Thus, the pharmaceutical composition of the present invention comprises a low dose of zastaprazan as described above, and when administered once a day, has the advantage of effectively and safely preventing the recurrence of peptic ulcer or the development of peptic ulcer caused by repeated long-term administration of NSAIDs.

[0056] In the present invention, the subject may be a person having an underlying disease such as a musculoskeletal and / or cardiovascular disease.

[0057] In the present invention, the pharmaceutical composition may include one or more pharmaceutical additives consisting of excipients, disintegrants, binders, and lubricants, but is not limited thereto.

[0058] In the present invention, the excipient may be at least one of microcrystalline cellulose, lactose monohydrate, anhydrous lactose, sucrose, D-mannitol, starch, corn starch, or light anhydrous silicic acid, but is not limited thereto.

[0059] In the present invention, the disintegrating agent may include starch or modified starch such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch; clay such as bentonite, montmorillonite, or veegum; celluloses such as hydroxypropyl cellulose or carboxymethyl cellulose; alginates such as sodium alginate or alginic acid; cross-linked celluloses such as croscarmellose sodium; gums such as guar gum or xanthan gum; cross-linked polymers such as crospovidone; and effervescent agents such as sodium bicarbonate or citric acid. These may be used alone or in combination of two or more thereof, but are not limited thereto.

[0060] In the present invention, the binder may be at least one 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.

[0061] 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, and the like. These may be used alone or in combination of two or more thereof, but are not limited thereto.

[0062] In the present invention, the pharmaceutical composition may be a solid oral preparation, but is not limited thereto.

[0063] In the present invention, the solid oral preparation may be any one of a tablet, a film-coated tablet, a capsule, a powder, a granule, a pill, a troche, an oral jelly, and an oral dissolving film, but is not limited thereto.

[0064] In particular, in the case of film-coated tablets, coating agents widely known in the art can be used, but are not limited thereto.

[0065] For use in preventing recurrence or development of peptic ulcers

[0066] The present invention provides the use of a pharmaceutical composition for preventing peptic ulcers induced by administration of NSAIDs comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0067] The present invention provides the use of a pharmaceutical composition for preventing recurrence of peptic ulcer induced by administration of NSAIDs comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0068] In the above 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 (free base form) or a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, specifically about 3.3, 6.6, 13.1, 26.2 or 52.4 mg of zastaprazan (free base form) or about 5 to 40 mg of zastaprazan citrate salt, specifically about 5 mg, 10 mg, 15 mg, 20 mg or 40 mg of zastaprazan citrate salt, and more specifically about 10 mg, 20 mg or 40 mg of zastaprazan citrate salt.

[0069] Thus, the pharmaceutical composition of the present invention comprises a low dose of zastaprazan as described above, and when administered once a day, has the advantage of effectively and safely preventing the recurrence of peptic ulcer or the development of peptic ulcer caused by repeated long-term administration of NSAIDs.

[0070] In the present invention, the pharmaceutical composition, subject, NSAIDs, peptic ulcer, etc. for use in preventing recurrence or onset of peptic ulcer can be applied in the same manner as described above, as long as they do not contradict each other.

[0071] Use for the manufacture of a drug for preventing recurrence or onset of peptic ulcer

[0072] The present invention provides a use for the manufacture of a medicament for preventing peptic ulcer induced by administration of NSAIDs, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0073] The present invention provides a use for the manufacture of a medicament for preventing recurrence of peptic ulcer induced by administration of NSAIDs, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0074] The composition of the present invention for the manufacture of a pharmaceutical agent may be mixed with an acceptable carrier, etc., and may additionally include other agents.

[0075] In the use for manufacturing a drug for preventing recurrence or onset of peptic ulcer of the present invention, the pharmaceutical composition, subject, peptic ulcer, etc. can be applied equally to the above-described contents as long as they do not contradict each other.

[0076] How to prevent recurrence or development of peptic ulcers

[0077] The present invention provides a method for preventing recurrence or development of peptic ulcer induced by administration of NSAIDs by administering to a subject a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, in a pharmaceutically effective amount.

[0078] In the above method, the pharmaceutical composition, subject, peptic ulcer, etc. of the present invention are substantially the same as those discussed above, unless they are contradictory to each other.

[0079] The term "pharmaceutically effective amount" in the present invention refers to an amount effective in preventing the recurrence or onset of peptic ulcer, for example, an amount of a pharmaceutical composition administered to a subject, which may include all amounts of a composition that prevents the occurrence or recurrence of peptic ulcer, alleviates symptoms, inhibits direct or indirect pathological consequences, prevents metastasis, reduces the rate of progression, alleviates or temporarily relieves a condition, or improves prognosis. In other words, the pharmaceutically effective amount may be interpreted to encompass all doses at which the recurrence and / or onset of peptic ulcer can be prevented by the composition.

[0080] Specifically, in the method for preventing recurrence and / or onset of peptic ulcer according to the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is administered to the subject once a day in an amount of 5 mg to 100 mg as zastaprazan (free base form), thereby preventing recurrence of peptic ulcer and preventing onset thereof caused by administration of NSAIDs. Specifically, the subject is administered once a day 1 mg to 100 mg, 2 mg to 60 mg or 3 mg to 40 mg of zastaprazan (free base form) as zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, specifically about 3.3, 6.6, 13.1, 26.2 or 52.4 mg of zastaprazan (free base form) as zastaprazan, 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 treat the recurrence of peptic ulcer or its development caused by long-term continuous repeated administration of NSAIDs. It can be prevented for a long time.

[0081] In the method for preventing recurrence or onset of peptic ulcer of the present invention, there is an advantage in that the recurrence and / or onset of peptic ulcer caused by taking NSAIDs can be prevented safely, long-term, and effectively without side effects despite continuous / long-term use of NSAIDs by administering the pharmaceutical composition to a subject.

[0082] Hereinafter, the present invention will be described in more detail through manufacturing examples and examples. These manufacturing examples and examples are intended to more specifically illustrate the present invention, and the scope of the present invention is not limited by these examples.

[0083] The active ingredient used in the following manufacturing examples and examples is zastaprazan citrate salt, which is conveniently named zastaprazan or code name JP-1366.

[0084] Manufacturing example.

[0085] Manufacturing Example 1. Manufacturing of zastaprazan citrate salt

[0086] 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 process. Specifically, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was obtained as described in Korean Patent Publication No. 10-1777971. The 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.

[0087] 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).

[0088] 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 dried under vacuum at about 30°C to 35°C to obtain a dried product. About 10 g of the dried product was taken and stirred with about 167 g of acetone. A solution of citric acid (about 5 g) dissolved in acetone (about 33 g) was slowly added dropwise thereto over 60 minutes and stirred at the same temperature for 1 hour. The mixture was cooled to approximately 20°C to 25°C and stirred for an additional 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.

[0089] 1 H NMR (400 MHz, 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)

[0090] Manufacturing Example 2. Manufacturing of JP-1366 tablets 10 mg (zastaprazan citrate salt 10 mg)

[0091] 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 salt (zastaprazan citrate salt) obtained according to the above Manufacturing 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 pressed directly to obtain tablets. Then, film-coated tablets were prepared by coating with 8.0 mg of Opadry white.

[0092] The film-coated tablet manufactured in this way is referred to as ‘JP-1366, 10 mg.’

[0093] Manufacturing Example 3. Manufacturing of JP-1366 tablets 20 mg (zastaprazan citrate salt 20 mg)

[0094] 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 salt (zastaprazan citrate salt) obtained according to the above Manufacturing 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 pressed directly to obtain tablets. Then, film-coated tablets were prepared by coating using 8.0 mg of Opadry 03B54445 pink.

[0095] The film-coated tablet manufactured in this way is referred to as ‘JP-1366, 20 mg.’

[0096] Manufacturing Example 4. Manufacturing of JP-1366 capsule 20 mg (zastaprazan citrate salt 20 mg)

[0097] 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 salt (zastaprazan citrate salt) obtained according to the above Manufacturing Example 1, 181.4 mg of D-mannitol, 12.4 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate. The mixture was filled into a hard capsule No. 1 using the capsule base to prepare a capsule preparation.

[0098] The capsules manufactured in this way are referred to as ‘JP-1366 Capsule 20 mg’.

[0099] Manufacturing Example 5. Zastaprazan 10 mg placebo

[0100] A 10 mg placebo containing zastaprazan was manufactured using the same method as in Manufacturing Example 2, except that the main ingredient, zastaprazan citrate salt, was not used. The film-coated tablet manufactured in this manner is referred to as 'JP-1366, 10 mg placebo'.

[0101] Manufacturing Example 6. Manufacturing of lansoprazole 15 mg formulation (control drug)

[0102] For lansoprazole preparations, 15 mg of Lanston Capsules (15 mg of lansoprazole) from Jeil Pharmaceutical Co., Ltd. were purchased and used. The 15 mg of Lanston Capsules purchased are referred to as "lansoprazole, 15 mg."

[0103] Manufacturing Example 7. Lansoprazole 15 mg placebo

[0104] A 15 mg lansoprazole placebo was manufactured using the same method as for manufacturing Lanstone capsules, except for the main ingredient, lansoprazole, and adding pharmaceutically acceptable excipients. The capsule manufactured in this way is referred to as 'lansoprazole, 15 mg placebo.'

[0105] Example 1. Evaluation of the antiulcer activity of zastaprazan in an animal model of acute peptic ulcer induced by naproxen.

[0106] To confirm the effect of zastaprazan on NSAID-induced peptic ulcer, the antiulcer activity of zastaprazan was evaluated in a rat gastric injury model induced by naproxen, an NSAID, and the antiulcer effect of zastaprazan was compared with that of esomeprazole.

[0107] 1. Test animals

[0108] Species and strains: Male SD (Sprague-Dawley) rat

[0109] Reason for selection of test system: The SD rat used in this study was selected because it is an appropriate experimental animal for the efficacy evaluation test and has accumulated abundant basic test data on the gastrointestinal mucosal damage model, so this data can be used for interpretation and evaluation of the test results.

[0110] Age at time of acquisition: approximately 7 weeks old

[0111] Quarantine and acclimatization: Approximately 7 days after receipt (only healthy animals are provided for testing)

[0112] Individual identification: Individuals are identified using the tagging method, and an individual identification card with the test number, test group, animal number, and sex is attached to each breeding box.

[0113] Age at time of test substance administration: approximately 8 weeks old

[0114] Number of animals ordered: 12

[0115] Number of animals used: 12

[0116] 2. Breeding conditions

[0117] Breeding Room: Clean Animal Room (Specific Pathogen Free)

[0118] Ventilation frequency: at least 10 times / hour

[0119] Temperature and humidity range: 22±4℃, 50±20% (RH)

[0120] Lighting time and intensity: 12 hours of lighting (lighting: 08:00~20:00), illumination: 150~300 Lux

[0121] Breeding box: polysulfonate material breeding box

[0122] Number of animals per cage: 2

[0123] Breeding management: Place autoclaved (121℃, 20 minutes) bedding (BETA CHIP®, Northeastern products Co., USA) on the bottom of the breeding box to dispose of feces and urine, and change it twice a week.

[0124] Type and name of feed: Irradiated solid feed for rodents (PMI LabDiet® 5053, USA)

[0125] Feed supply: Ad libitum feeding using a feeder

[0126] Type of drinking water: tap water sterilized with ultraviolet sterilizer and high-pressure steam after reverse osmosis treatment

[0127] Water supply: Change water once or twice a week. Use a 500 mL rat-specific water bottle. Clean and sterilize the bottle before use. Drinking water should be purified and UV-sterilized.

[0128] 3. Test method

[0129] To induce gastric damage in laboratory animals, naproxen was administered orally at a dose of 40 mg / kg once daily for 5 days. The administered volume was 5 ml / kg, and 4 hours after the final naproxen administration, the animals were anesthetized, laparotomy was performed, and the stomachs were removed.

[0130] Specifically, 40 mg / kg of naproxen was orally administered once a day for 5 days to non-fasted SD male rats, and the stomachs were removed 4 hours after the last naproxen administration.

[0131] Group composition and administration volume setting: The test group composition and administration volume are as follows.

[0132]

[0133] Administration site and method: The test substance (zastaprazan, JP-1366) and the reference substance (esomeprazole) are administered orally in parallel with naproxen administration. The individual dosage is calculated based on the pre-administration body weight, and 5 ml of the solution is administered orally per kg of body weight. Administration of the test substance and reference substance and naproxen are performed at 30-minute intervals.

[0134] Dosage frequency and administration period: Once a day, for 5 days (total of 5 times)

[0135] 4. Observation and inspection items

[0136] A. Observation of general symptoms

[0137] Before and after administration of the test substance, observe each animal for general symptoms and the occurrence of death / moribund animals. Records are maintained only for animals exhibiting specific symptoms (normal cases are not recorded).

[0138] B. Weight measurement

[0139] Upon acquisition, separation of groups, and prior to administration of the test substance, individual body weights are measured. To minimize errors, the same scale is used for each measurement.

[0140] D. Autopsy and measurement of the area of ​​gastric damage

[0141] After the test, the stomach damage caused by the test substance is evaluated by the Ulcer index. 4 hours after the last naproxen administration, the stomach is removed after anesthesia and bleeding. The removed stomach is incised along the greater trochanter, the contents are removed, washed cleanly in saline solution, spread well with a cotton swab, fixed with a pin, and then photographed. The photographed stomach is used to measure the damaged area and the total stomach area using an image program (Leica Application Suite V4), and the Ulcer index (%) = damaged area (mm) 2 ) / Total area (mm) 2 ) * Calculate as 100.

[0142] A. Histopathological examination

[0143] The extracted gastric tissue is fixed in 10% buffered neutral formalin. The fixed tissue is then trimmed to a certain thickness and, after undergoing a standard tissue processing procedure, paraffin-embedded to produce 4-5 ㎛ tissue sections. Then, hematoxylin & eosin (H&E) staining is performed. The production of H&E stained slides and histopathological findings are performed by an external institution.

[0144] 5. Statistical processing

[0145] The experimental results were statistically analyzed using Mann-Whitney analysis using a commercial statistical processing program (IBM SPSS statistics version 25.0).

[0146] 6. Results

[0147] Referring to Figure 1, the group treated with the test substance, zastaprazan (JP-1366), showed a rapid decrease in ulcer area in the naproxen-induced peptic ulcer model, confirming that the test substance, zastaprazan (JP-1366), exhibited excellent antiulcer activity.

[0148] In addition, it was confirmed that the antiulcer efficacy of the test substance, zastaprazan (JP-1366), was superior to that of the control substance, esomeprazole.

[0149] Therefore, it can be confirmed that the test substance, zastaprazan (JP-1366), can prevent peptic ulcers caused by NSAIDs.

[0150] In addition, in the case of Example 1, an anti-ulcer effect experiment was conducted when NSAIDs were administered to subjects in a non-fasting state, the same as when administered to actual humans, and it can be seen that the efficacy in preventing peptic ulcers caused by NSAID administration was confirmed in humans as well.

[0151] Example 2. Pharmacokinetic (PK) interaction and safety assessment between zastaprazan and aceclofenac, meloxicam, or naproxen.

[0152] Zastaprazan is a potassium-competitive acid secretion inhibitor that reversibly inhibits gastric H+, K+-adenosine triphosphatase and exhibits a faster onset of action than proton pump inhibitors. Zastaprazan can be used not only for the treatment of acid-related gastric disease but also to prevent gastric damage caused by nonsteroidal anti-inflammatory drugs. To confirm this, we conducted a clinical trial to evaluate the pharmacodynamic (PK) interactions and safety of zastaprazan with aceclofenac, meloxicam, or naproxen in healthy subjects.

[0153] - PART 1: Pharmacodynamic (PK) interaction between zastaprazan and aceclofenac

[0154] - PART 2: Pharmacodynamic (PK) Interactions Between Zastaprazan and Meloxicam

[0155] - PART 3: Pharmacodynamic (PK) Interactions Between Zastaprazan and Naproxen

[0156] 1. Test drug

[0157] A. Test drug 1 - Zastaprazan 40 mg

[0158] JP-1366, 20 mg 2 capsules (Zastaprazan citrate salt 40 mg)

[0159] B. Test drug 2 - Aceclofenac 100 mg

[0160] Airtal tablets (aceclofenac 100 mg)

[0161] D. Test drug 3 - Meloxicam 15 mg

[0162] Mobic Capsule 15 mg (Meloxicam 15 mg)

[0163] A. Test drug 4 - Naproxen 500 mg

[0164] Naproxen F tablets (naproxen 500 mg)

[0165] 2. Test method

[0166] <PART 1>

[0167] Subjects who volunteered for PART 1 were assigned a subject number on the day before the first administration of the clinical trial drug in Period 1 (-1d), and then received 1 tablet of aceclofenac on Day 1 of Period 1, 2 capsules of JP-1366 on Days 4 to 8 of Period 2, and 2 capsules of JP-1366 and 1 tablet of aceclofenac on Day 9 of Period 3. Blood samples were drawn from each subject at designated times for pharmacokinetic evaluation of the clinical trial drug, and all subjects underwent safety evaluation according to the designated schedule.

[0168] All subjects who completed the clinical trial underwent a post-study visit on one day between 14 and 20 days, including vital sign measurement, physical examination, adverse reaction check, confirmation of prior / concurrent medication, clinical laboratory tests, and electrocardiogram tests.

[0169] <PART 2>

[0170] Subjects who volunteered for PART 2 were assigned a subject number on the day before the first administration of the clinical trial drug in Period 1 (-1d), and then received two capsules of JP-1366 on days 1 to 5 of Period 1, one capsule of meloxicam on days 15 to 19 of Period 2, and two capsules of JP-1366 and one capsule of meloxicam on days 22 to 26 of Period 3. Blood samples were drawn from each subject at designated times for pharmacokinetic evaluation of the clinical trial drug, and all subjects underwent safety evaluation according to the designated schedule.

[0171] All subjects who completed the clinical trial underwent a post-study visit on one day between 31 and 37 days, including vital sign measurement, physical examination, adverse reaction check, confirmation of prior / concurrent medication, clinical laboratory tests, and electrocardiogram tests.

[0172] <PART 3>

[0173] Subjects who volunteered for PART 3 were assigned a subject number on the day before the first administration of the clinical trial drug in Period 1 (-1d), and then received two capsules of JP-1366 on days 1 to 5 of Period 1, one tablet of naproxen on days 15 to 19 of Period 2, and two capsules of JP-1366 and one tablet of naproxen on days 22 to 26 of Period 3. Blood samples were drawn from each subject at designated times to evaluate the pharmacokinetics of the clinical trial drug, and all subjects underwent safety evaluation according to the designated schedule.

[0174] All subjects who completed the clinical trial underwent a post-study visit on one day between 31 and 37 days, including vital sign measurement, physical examination, adverse reaction check, confirmation of prior / concurrent medication, clinical laboratory tests, and electrocardiogram tests.

[0175] 3. Pharmacokinetic (PK) analysis

[0176] Blood samples for pharmacokinetic evaluation of zastaprazan (JP-1366) were collected at scheduled times.

[0177] A. Part 1 - 22 subjects

[0178] (1) Aceclofenac 100 mg (A)

[0179] : 1d 0h (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12h post-dose

[0180] (2) Zastaprazan 40 mg (Z)

[0181] : 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

[0182] (3) Zastaprazan 40 mg and aceclofenac 100 mg (Z+A)

[0183] : 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)

[0184] Part 2 - 22 subjects

[0185] (1) Zastaprazan 40 mg (Z)

[0186] : 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)

[0187] (2) Meloxicam 15 mg (M)

[0188] : 19d 0h (pre-dose), 1, 2, 3, 4, 5, 6, 8, 12, 24h (20d 0h) post-dose

[0189] (3) Zastaprazan 40 mg and meloxicam 15 mg (Z+M)

[0190] : 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

[0191] Part 3 - 22 subjects

[0192] (1) Zastaprazan 40 mg (Z)

[0193] : 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)

[0194] (2) Naproxen 500 mg (N)

[0195] : 19d 0h (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12h post-dose

[0196] (3) Zastaprazan 40 mg and naproxen 500 mg (Z+N)

[0197] : 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

[0198] 4. Results

[0199] a. PART 1 - See Table 1 and Figures 2 and 3

[0200] Zastaprazan C of Z+A (zastaprazan 40 mg and aceclofenac 100 mg) to Z (zastaprazan 40 mg) max,SS and AUC T,SS The geometric mean ratio (GMR) [90% confidence interval, CI] for were 1.0868 (0.9554-1.2362) and 0.9490 (0.9096-0.9902), respectively.

[0201] Aceclofenac C of Z+A (zastaprazan 40 mg and aceclofenac 100 mg) to A (aceclofenac 100 mg) max,SS and AUC T,SS The GMR [90% CI] for were 1.1895 (1.0429-1.3568) and 1.0295 (0.9803-1.0812), respectively.

[0202] [Table 1]

[0203]

[0204] (Table 1 above shows the pharmacokinetic parameters of zastaprazan (Z) and aceclofenac (A), and the data are expressed as mean ± standard deviation.)

[0205] B. PART 2 - See Table 2 and Figures 4 and 5.

[0206] Zastaprazan C of Z+M (zastaprazan 40 mg and meloxicam 15 mg) to Z (zastaprazan 40 mg) max,SS and AUC T,SS The GMR [90% CI] for were 1.0926 (0.9387-1.2717) and 1.3332 (1.1494-1.5463), respectively.

[0207] Meloxicam C of Z+M (zastaprazan 40 mg and meloxicam 15 mg) to M (meloxicam 15 mg) max,SS and AUC T,SS The GMR [90% CI] for were 1.0756 (0.9916-1.1668) and 1.0477 (0.9976-1.1002), respectively.

[0208] [Table 2]

[0209]

[0210] (Table 2 above shows the pharmacokinetic parameters of zastaprazan (Z) and meloxicam (M), and the data are expressed as mean ± standard deviation.)

[0211] PART 3 - See Table 3 and Figures 6 and 7.

[0212] Zastaprazan C of Z+N (zastaprazan 40 mg and naproxen 500 mg) to Z (zastaprazan 40 mg) max,SS and AUC T,SS The GMR [90% CI] for were 0.9148 (0.7956-1.0518) and 1.1089 (0.9835-1.2503), respectively.

[0213] Naproxen C of Z+N (zastaprazan 40 mg and naproxen 500 mg) to N (naproxen 500 mg) max,SS and AUC T,SSThe GMR [90% CI] for were 1.0491 (1.0088-1.0910) and 1.0155 (0.9900-+1.0417), respectively.

[0214] [Table 3]

[0215]

[0216] (Table 3 above shows the pharmacokinetic parameters of zastaprazan (Z) and naproxen (N), and the data are expressed as mean ± standard deviation.)

[0217] A. Summary

[0218] No clinically significant PK interactions were observed between zastaprazan and aceclofenac, meloxicam, or naproxen without safety concerns.

[0219] Example 3. Evaluation of the efficacy and safety of zastaprazan administration in preventing nonsteroidal anti-inflammatory drug-induced peptic ulcer.

[0220] 1. Subject selection

[0221] We designed a multicenter, parallel-design, double-blind, randomized, active-controlled, non-inferiority clinical trial to evaluate the efficacy and safety of zastaprazan in preventing gastroduodenal ulcers in patients with nonsteroidal anti-inflammatory drug-induced peptic ulcers.

[0222] Selection criteria

[0223] Applicants must meet all of the following criteria:

[0224] 1. Adult men and women aged 19 or older as of the date of written consent

[0225] 2. Those diagnosed with musculoskeletal diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis during screening and requiring continuous administration of NSAIDs (aceclofenac, meloxicam, naproxen, celecoxib) for more than 24 weeks.

[0226] 3. Those who have one or more of the following risk factors for ulcer development during screening:

[0227] 1) 60 years of age or older

[0228] 2) Those who have a history of peptic ulcer as documented by upper gastrointestinal endoscopy or have ulcer scars as confirmed by upper gastrointestinal endoscopy (performed within 10 days of randomization)

[0229] 3) Concomitant use of low-dose aspirin (aspirin <81 mg - 325 mg / day) (However, those with this risk factor must continue taking low-dose aspirin during the clinical trial period)

[0230] 4) Concomitant use of Prednisone (or corticosteroids of equivalent dose or less) at 10 mg / day or less (however, those with this risk factor must maintain corticosteroid administration at the corresponding dose during the clinical trial period.)

[0231] 4. Those who have fully understood this clinical trial and voluntarily agreed in writing to participate in the clinical trial.

[0232] Exclusion criteria

[0233] The subject must not fall under any of the following criteria:

[0234] 1. Those who cannot undergo endoscopy

[0235] 2. Those who have active ulcer (A1, A2) or healing ulcer (H1, H2) in the stomach or duodenum according to the Sakita-Miwa classification* as of the screening time based on the results of an upper gastrointestinal endoscopy.

[0236] * Sakita-Miwa classification

[0237] 1) Active ulcer

[0238] (1) Active stage (A1): The white spot is thick and protrudes from the surrounding area. Small hemorrhages or clots are frequent. The surrounding area is red, swollen, and eroded, and the inflammation is severe, and the margins are raised and large.

[0239] (2) Active phase (A2): The protruding white patches disappear, and their margins become clear. The surrounding inflammation also becomes considerably milder, and the protrusions are somewhat reduced. Concentrated mucosal folds appear. Regenerative epithelium is present, but very minimal.

[0240] 2) Healing ulcer

[0241] (1) Healing stage (H1): The ulcer becomes shallow, the white coating is clear, and its margins are smooth. The regenerated epithelium becomes clear, the main lesion is almost completely gone, and the mucosal folds reach the margins of the white coating and become concentrated.

[0242] (2) Healing phase (H2): The ulcer shrinks significantly. The white coating becomes lighter. The width of the regenerated epithelium increases.

[0243] 3) Cicatricial ulcer

[0244] (1) Cicatricial stage (S1): Mucosal loss is reduced, but erythema of the regenerated epithelium remains. A small, discolored spot is often visible in the center. Mucosal folds extend gently to the center.

[0245] (2) Scarring stage (S2): Redness disappears, the regenerated epithelium becomes thick and has a color very similar to the surrounding mucosa. In some cases, the concentration of wrinkles disappears, leaving only the concentrated appearance of the mucosa.

[0246] 3. Troops

[0247] 1) Those with a history of malignant tumor within the past 5 years as of the screening date. However, those with a history of gastrointestinal malignancy are excluded regardless of the period of time.

[0248] 2) Those with warning symptoms that suggest a malignant disease of the gastrointestinal tract (dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stool, etc.) (However, those who have tested negative for malignancy through endoscopic examination and esophageal biopsy are excluded)

[0249] 3) Patients with gastroesophageal varices, Barrett's esophagus (greater than 3 cm), esophageal dysplasia, esophageal stricture, ulcerative stricture, or acute gastrointestinal bleeding as a result of screening upper gastrointestinal endoscopy.

[0250] 4) Those with Zollinger-Ellison syndrome or other gastric acid secretion disorders or a history of such disorders.

[0251] 5) Those with a current or suspected history of inflammatory bowel disease (IBD), including pancreatitis, primary esophageal motility disorder, irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, and Behcet's enteritis.

[0252] 6) Those 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)

[0253] 7) Those who tested positive for H. pylori in a screening test

[0254] 8) Those with clinically significant diseases of the blood, liver, kidney, cardiovascular, respiratory, endocrine, urinary, neuropsychiatric, immune, or hematological malignancies.

[0255] 9) Those with a history of drug or alcohol abuse within one year of the screening date

[0256] 4. Clinical laboratory testing

[0257] 1) Those who meet any of the following criteria as a result of screening

[0258] ① Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels exceed twice the upper limit of normal (ULN).

[0259] ② Total Bilirubin level exceeds twice the upper limit of normal (ULN)

[0260] ③ Alkaline Phosphatase (ALP) or γ-glutamyl Transpeptidase (γ-GTP) levels exceeding twice the upper limit of normal (ULN)

[0261] 2) Those who have tested positive for any of the following: Human Immunodeficiency Virus (HIV) antigen / antibody test, Hepatitis B Surface Antigen (HBsAg), Hepatitis C Antibody (Anti-HCV), or Syphilis test (Venereal Disease Research Laboratory, VDRL) results.

[0262] However, the following cases may be included.

[0263] 2-1) Those who are HBsAg positive and have an HBV-DNA level of less than 100,000 IU / mL

[0264] 2-2) Those who are HCV-Ab positive but HCV-RNA negative

[0265] 3) Those who were found to have clinically significant abnormalities (Clinically Significant, CS) in electrocardiograms during screening

[0266] 5. Allergies and drug hypersensitivity reactions

[0267] 1) Persons known to have hypersensitivity to clinical trial drugs and their components

[0268] 2) Those with a history of clinically significant allergic disease (excluding mild allergic rhinitis that does not require medication) or hypersensitivity to other drugs (non-steroidal anti-inflammatory drugs, aspirin, antibiotics, etc.) (asthma, acute rhinitis, nasal polyps, angioedema, urticaria, allergic reaction, etc.)

[0269] 6. Contraindicated drugs and treatments

[0270] 1) Those who must continuously take corticosteroids, antiplatelet agents, or anticoagulants during this clinical trial [However, the following cases are permitted.]

[0271] ① Low-dose aspirin (81 mg or more to 325 mg or less / day) taken for the purpose of preventing cardiovascular disease before participating in this clinical trial

[0272] ② Administration of prednisone 10 mg / day (or an equivalent dose or less of corticosteroid)

[0273] ③ Topical corticosteroids used to treat musculoskeletal diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis

[0274] 2) Those who are taking or need to take drugs that are contraindicated for concomitant use in this clinical trial (However, those who are taking contraindicated drugs may participate after a one-week wash-out period. However, those taking the contraindicated drugs listed below may participate in this clinical trial after the corresponding wash-out period has elapsed, depending on the half-life of the drug.)

[0275] Drugs with a half-life greater than 24 hours: 2 weeks

[0276] If the period equivalent to five times the half-life exceeds two weeks: five times the wash-out half-life of the drug

[0277] 7. Pregnant or lactating women or those who tested positive during screening

[0278] 8. Contraception

[0279] 1) Subjects and their spouses (or partners) who are not using a medically acceptable method of contraception during the clinical trial. "Medically acceptable methods of contraception" include:

[0280] ① Use of an intrauterine device (IUD) with a proven pregnancy failure rate

[0281] ② Use of double-barrier contraception (male condom and closure cap, diaphragm or cervical cap) and simultaneous use of spermicide

[0282] ③ Infertility treatment (vasectomy, salpingectomy and ligation, hysterectomy)

[0283] 9. Those with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

[0284] 10. Those who participated in another clinical trial within 4 weeks prior to participating in this clinical trial and were administered or applied any clinical trial drug or medical device at least once.

[0285] 11. Those who are deemed unsuitable for participation in this clinical trial based on the medical opinion of other investigators.

[0286] 2. Dosage, administration period, and administration method

[0287] Subjects will be administered the clinical trial drug assigned to the randomly assigned group, one tablet and one capsule once a day before meals, for 24 weeks starting from the day following the randomization date, orally at a consistent time if possible.

[0288] [Table 4]

[0289]

[0290] (In Table 4 above, ● represents JP-1366, 10 mg, ○ represents JP-1366, 10 mg placebo, ▲ represents lansoprazole, 15 mg, and △ represents lansoprazole, 15 mg placebo.)

[0291] Combination NSAIDs

[0292] Subjects will be administered one type of NSAID among aceclofenac, meloxicam, naproxen, and celecoxib at the investigator's discretion from the date of randomization, and the type and dosage of concomitant NSAIDs must be maintained without change during the clinical trial period.

[0293] 3. Clinical trial method

[0294] [Revised on January 25, 2024, pursuant to Article 91 of the Regulations] Subjects will visit the clinical trial institution at 4, 12, and 24 weeks from the randomization date to undergo efficacy and safety assessments according to the scheduled schedule. The efficacy assessment will determine whether peptic ulcers or NSAID-related gastrointestinal symptoms occur.

[0295] [Revised 25.01.2024 under Article 91 of the Rules] Information on adverse events (AEs), vital signs (blood pressure, pulse, body temperature), physical examinations, and clinical laboratory tests (hematology, blood chemistry, and urine tests) is collected for safety assessment.

[0296] If a peptic ulcer is identified by endoscopic examination during the clinical trial, participation in the trial will be terminated early at that point. If an ulcer is identified and treatment is terminated early, this is considered an EOT. A follow-up visit will be conducted after the EOT.

[0297] 4. Validity evaluation variables

[0298] A. Primary efficacy endpoint:

[0299] Cumulative proportion of subjects with peptic ulcers* up to 24 weeks (%)

[0300] * Newly discovered scarring stage ulcers other than active stage / healing stage ulcers or scars identified at the time of screening according to the Sakita-Miwa classification

[0301] B. Secondary efficacy endpoints:

[0302] Proportion (%) of subjects with endoscopic bleeding of the stomach or duodenum** through week 24

[0303] **Those who fall into Class 1 or 2 according to the Forrest Classification

[0304] D. Exploratory evaluation variables

[0305] 1. Proportion of subjects with peptic ulcer disease up to 12 weeks (%)

[0306] 2. Proportion (%) of subjects with endoscopic bleeding** of the stomach or duodenum by week 12

[0307] 3. Incidence of peptic ulcers (%) by type of NSAIDs (aceclofenac, meloxicam, naproxen, celecoxib)

[0308] 4. Rate of occurrence of peptic ulcers according to risk factors for peptic ulcers

[0309] 5. Rate of occurrence of peptic ulcers according to the number of risk factors for peptic ulcers

[0310] 6. Rate of change in serum gastrin concentration compared to baseline

[0311] 7. Rate (%) of gastrointestinal symptoms through questionnaire (00) at 4, 12, and 24 weeks compared to baseline

[0312] 8. Changes in blood hemoglobin (Hb) concentration at weeks 4, 12, and 24 compared to baseline

[0313] 5. Stability evaluation variables

[0314] - Abnormal case

[0315] - Vital signs

[0316] - Physical examination

[0317] - Clinical laboratory test results

[0318] - Electrocardiogram test

[0319] 6. Definition of analysis group and statistical analysis method

[0320] Analysis group definition

[0321] The analysis group is divided into the following three groups. The validity evaluation analysis is performed based on the Full Analysis Set (FAS) and Per Protocol Set (PPS), with the FAS as the primary analysis group. The safety analysis is performed on the Safety Set (safety assessment group).

[0322] 1. FAS

[0323] This refers to the group of subjects who received the clinical trial drug at least once and underwent primary efficacy evaluation at least once in this clinical trial.

[0324] 2. PPS

[0325] It refers to the group of all subjects included in the FAS who do not have any serious violations of the clinical trial protocol.

[0326] 3. Safety Set (Safety Assessment Group)

[0327] This refers to the group of subjects who received the clinical trial drug at least once in this clinical trial.

[0328] Statistical analysis methods

[0329] A. Primary efficacy evaluation variable

[0330] Cumulative proportion (%) of subjects developing peptic ulcers up to 24 weeks

[0331] : The proportion of subjects developing peptic ulcers by 24 weeks after drug administration compared to the baseline is presented by treatment group, and to compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is 20% or more of the total, a Fisher's exact test is performed.

[0332] Additionally, we will use logistic regression analysis to determine whether there are differences between treatment groups when adjusting for the type of nonsteroidal anti-inflammatory drugs (aceclofenac, meloxicam, naproxen, celecoxib) being administered to the stratified subjects and whether aspirin or / and prednisone was administered (used / unused) among the risk factors for ulcer development, regarding the occurrence of peptic ulcer at 24 weeks.

[0333] B. Secondary efficacy evaluation variables

[0334] Proportion (%) of subjects with endoscopic bleeding of the stomach or duodenum by week 24

[0335] : The proportion of subjects who developed endoscopic bleeding in the stomach or duodenum at 12 and 24 weeks after drug administration compared to the baseline is presented by treatment group. To compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is 20% or more of the total, a Fisher's exact test is performed.

[0336] D. Exploratory evaluation variables

[0337] 1. Proportion of subjects with peptic ulcer disease up to 12 weeks (%)

[0338] : The proportion of subjects developing peptic ulcers by 12 weeks after drug administration compared to the baseline is presented by treatment group, and to compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is 20% or more of the total, a Fisher's exact test is performed.

[0339] 2. Proportion (%) of subjects with endoscopic bleeding of the stomach or duodenum by week 12

[0340] : The proportion of subjects who developed endoscopic bleeding in the stomach or duodenum at 12 and 24 weeks after drug administration compared to the baseline is presented by treatment group. To compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is 20% or more of the total, a Fisher's exact test is performed.

[0341] 3. Incidence of peptic ulcers (%) by type of NSAIDs (aceclofenac, meloxicam, naproxen, celecoxib)

[0342] 4. Rate of occurrence of peptic ulcers according to risk factors for peptic ulcers (%)

[0343] : The incidence rate of peptic ulcers according to the risk factor for ulcer development is presented by treatment group, and to compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is more than 20% of the total, a Fisher's exact test is performed.

[0344] 5. Rate of occurrence of peptic ulcers according to the number of risk factors for peptic ulcers (%)

[0345] 6. Changes in gastrin levels at 4, 12, and 24 weeks compared to baseline

[0346] Descriptive statistics (mean, standard deviation, median, minimum, maximum) are provided for gastrin levels at 4, 12, and 24 weeks and for changes in gastrin levels from baseline to 4, 12, and 24 weeks after drug administration. To compare differences between treatment groups, a two-sample t-test is performed if the normality assumption is met, and a Wilcoxon rank sum test is performed if the normality assumption is not met. In addition, if changes in each visit's test values ​​compared to the baseline are not compared, Wilcoxon's signed rank test is used for analysis.

[0347] 7. Rate (%) of gastrointestinal symptoms through questionnaires at 4, 12, and 24 weeks compared to baseline

[0348] The proportion of subjects free of NSAID-related gastrointestinal symptoms (such as acid reflux, upper abdominal pain or discomfort, or indigestion) at 4, 12, and 24 weeks after drug administration is presented by treatment group. To compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is 20% or more of the total, a Fisher's exact test is performed.

[0349] 8. Change in blood hemoglobin (Hb) concentration at weeks 4, 12, and 24 compared to baseline (%)

[0350] Descriptive statistics (mean, standard deviation, median, minimum, maximum) are provided for the blood hemoglobin levels at 4, 12, and 24 weeks and the changes in hemoglobin levels from baseline to 4, 12, and 24 weeks after drug administration. To compare whether there are differences between treatment groups, a two-sample t-test is performed if the assumption of normality is met, and a Wilcoxon rank sum test is performed if the assumption of normality is not met. In addition, if the changes in the test values ​​at each visit compared to the baseline are not compared, Wilcoxon's signed rank test is used for analysis.

[0351] *If medication compliance is less than 80%, it is considered IP non-compliance.

[0352] A. Safety evaluation variables

[0353] 1. Adverse reactions

[0354] The number of subjects with adverse reactions, percentage, 95% confidence interval, and number of occurrences are presented by treatment group. To compare whether there is a difference between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is more than 20% of the total, a Fisher's exact test is performed.

[0355] The number of subjects who developed adverse reactions, the percentage and 95% confidence interval, and the number of occurrences are presented by treatment group for the severity of adverse reactions, causality, actions taken for clinical trial drugs, and treatment and results of adverse events. To compare whether there are differences between treatment groups, if the number of cells with an expected frequency of less than 5 is less than 20% of the total, a Chi-square test is performed, and if the number of cells with an expected frequency of less than 5 is more than 20% of the total, a Fisher's exact test is performed.

[0356] 2. Vital signs, physical examination, and clinical laboratory tests

[0357] For continuous data, descriptive statistics (mean, standard deviation, median, minimum, maximum) are provided for each visit. To compare differences between treatment groups, a two-sample t-test is performed if the assumption of normality is met. If the assumption of normality is not met, the Wilcoxon rank sum test is performed. Additionally, if changes in each visit's test values ​​compared to the baseline are not compared, the Wilcoxon's signed rank test is used for analysis.

[0358] For categorical data, describe the frequency and proportion for each visit, and for comparison of differences between treatment groups, if the expected frequency is less than 5 and less than 20% of the total cells, perform the Chi-square test, and if the expected frequency is less than 5 and more than 20% of the total cells, perform the Fisher's exact test. The values ​​at baseline and at each visit are divided into normal / abnormal categories, and the McNemar's Test is used to test whether the normal / abnormal proportion changed before and after administration of the clinical trial drug.

[0359] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will 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 above peptic ulcer is a pharmaceutical composition caused by the administration of NSAIDs (Nonsteroidal anti-inflammatory drugs, NSAID).

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

3. In the first paragraph, the pharmaceutical composition comprises 1 mg to 100 mg of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

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

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

6. A pharmaceutical composition according to claim 1, wherein the subject of administration of the pharmaceutical composition is a subject who has experienced peptic ulcer caused by administration of NSAIDs.

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

8. A pharmaceutical composition according to claim 1, wherein the NSAIDs are acetic acid-derived non-selective NSAIDs, enolic acid-derived non-selective NSAIDs, phenamic acid-derived non-selective NSAIDs, p-amino phenol-derived non-selective NSAIDs, propionic acid-derived non-selective NSAIDs, salicylic acid-derived non-selective NSAIDs, selective COX-2 inhibitors, or mixtures thereof.

9. In the 8th paragraph, the acetic acid-derived non-selective NSAIDs are Aceclofenac, Acemetacin, Actarit, Alcofenac, Amfenac, Clometacin, Diclofenac, Etodolac, Felbinac, Fenclofenac, Indometacin, Ketorolac, Metiazinic acid, Mofezolac, Nabumetone, Naproxen, Oxametacin, Sulindac, Zomepirac or any combination thereof; The above enolic acid derived NSAIDs are Droxicam, Isoxicam, Lornoxicam, Meloxicam, Piroxicam, Tenoxicam or any combination thereof; The above fenamic acid derived NSAIDs are flufenamic acid, mefenamic acid, meclofenamic acid, tolfenamic acid or any combination thereof; The above p-aminophenol derived NSAIDs are paracetamol, phenacetin or any combination thereof; The above propionic acid derived NSAIDs are Alminoprofen, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, Ibuprofen, Indoprofen, Ketoprofen in pharmaceutically acceptable form, Loxoprofen, Oxaprozin, Pranoprofen, Suprofen or any combination thereof; The above salicylic acid derived NSAIDs are 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. A pharmaceutical composition comprising one or more of the following.

10. A pharmaceutical composition according to claim 1, wherein the NSAIDs are at least one selected from the group consisting of naproxen, aceclofenac, meloxicam, and celecoxib.

11. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered once a day.

12. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated as a solid oral preparation.

13. Use of a pharmaceutical composition for preventing peptic ulcer induced by administration of NSAIDs comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

14. Use of a pharmaceutical composition for preventing recurrence of peptic ulcer induced by administration of NSAIDs comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

15. Use for the manufacture of a medicament for preventing peptic ulcer induced by administration of NSAIDs comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

16. Use for the manufacture of a medicament for preventing recurrence of peptic ulcer induced by administration of NSAIDs comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

17. A method for preventing recurrence or development of peptic ulcer induced by administration of NSAIDs by administering to a subject a pharmaceutically effective amount of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.