Composition for eradicating helicobacter pylori comprising zastaprazan or pharmaceutically acceptable salt thereof

Abstract

Disclosed is a composition for eradicating helicobacter pylori, comprising zaltaprazan or a pharmaceutically acceptable salt thereof.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480075664.6 (22) Application Date 2024.11.28 (30) Priority Data 10-2023-0169710 2023.11.29 KR (85) PCT International Application Entering National Phase Date 2026.05.28 (86) PCT International Application Application Data PCT / KR2024 / 019081 2024.11.28 (87) PCT International Application Publication Data WO2025 / 116549 KO 2025.06.05 (71) Applicant: First Pharmaceutical Co., Ltd. Address: South Korea Applicant: Anconic Therapeutics Co., Ltd. (72) Inventors: Kim John, Cha Hyun-joo, Han Sang-woo (74) Patent Agency: Beijing Kangxin Intellectual Property Agency Co., Ltd. 11240 Patent Attorney: Chen Zhiyu (51) Int.Cl. A61K 31 / 437 (2006.01) A61P 31 / 10 (2006.01) A61P 1 / 04 (2006.01) (54) Invention Title: Composition for eradicating Helicobacter pylori containing zataprazan or a pharmaceutically acceptable salt thereof (57) Abstract: A composition for eradicating Helicobacter pylori containing zataprazan or a pharmaceutically acceptable salt thereof is disclosed. Claims (1 page), Description (20 pages), CN 122295096 A, 2026.06.26, CN 1 22 29 50 96 A 1. A composition for the eradication of Helicobacter pylori, the composition comprising zataprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof. 2. The composition for the eradication of Helicobacter pylori according to claim 1, wherein the pharmaceutically acceptable salt of zataprazan is zataprazan citrate. 3. The composition for the eradication of Helicobacter pylori according to claim 1, wherein the composition for eradication comprises a pharmaceutically acceptable salt of zataprazan in an amount of 10 mg, 20 mg, or 40 mg. 4. The composition for the eradication of Helicobacter pylori according to claim 1, wherein the composition for eradication is applied once to three times daily. 5. The composition for the eradication of Helicobacter pylori according to claim 1, wherein the composition for eradication is applied once daily. 6. The composition for Helicobacter pylori eradication according to claim 1, wherein the composition for eradication is formulated as a solid oral preparation.7. The composition for Helicobacter pylori eradication according to claim 6, wherein the solid oral formulation is any one of tablets, film-coated tablets, capsules, powders, granules, pills, lozenges, oral gels, and oral dissolving film formulations. 8. A pharmaceutical composition for treating Helicobacter pylori, comprising zataprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvation, or a mixture thereof. 9. A method for eradicating Helicobacter pylori, the method comprising administering to a subject in need a pharmaceutically effective amount of the composition comprising a therapeutically effective amount of zataprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvation, or a mixture thereof. 10. Use of a composition in eradicating Helicobacter pylori, the composition comprising zataprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvation, or a mixture thereof. 11. Use of a composition in the preparation of a medicament for Helicobacter pylori eradication, the composition comprising zataprazan, its pharmaceutically acceptable salt thereof, its hydrate or solvation, or a mixture thereof. Claims 1 / 1 Page 2 CN 122295096 A Composition for Eradication of Helicobacter pylori Containing Zastaprazan or a Pharmaceutically Acceptable Salt thereof Technical Field

[0001] The present invention relates to a composition for eradication of Helicobacter pylori (H. pylori) containing zastaprazan or a pharmaceutically acceptable salt thereof, and more specifically, to a composition for eradication of Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein the composition exhibits therapeutic efficacy against gastroesophageal reflux disease and / or peptic ulcers due to its own eradication action independent of Helicobacter pylori infection, and is quite likely to show high efficacy in patients infected with Helicobacter pylori. Background Art

[0002] Helicobacter pylori is a Gram-negative spirochete that lives in the gastric mucosa of humans, and it is classified as a Group 1 carcinogen by the World Health Organization (WHO), and about half of the adults in South Korea are infected. Helicobacter pylori is a bacterium that parasitizes the gastric mucosa and continues to grow; it will not disappear on its own unless it receives appropriate treatment.

[0003] The route of infection for Helicobacter pylori is not well understood, but human-to-human transmission is known. It is understood that infection is closely related to the unique lifestyle of Koreans, thus increasing their risk of exposure to Helicobacter pylori infection.

[0004] Helicobacter pylori has been identified as a cause of atrophic gastritis, intestinal metaplasia, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer, and is also known to be associated with functional dyspepsia, iron deficiency anemia of unknown etiology, and chronic idiopathic thrombocytopenic purpura.

[0005] Results of a multicenter study of asymptomatic adults in South Korea showed a serological prevalence of 51.0% in 2015, indicating a steady decline compared to the past. This is attributed not only to proactive treatment but also to improvements in economic conditions and sanitation.

[0006] First-line eradication of Helicobacter pylori involves the use of gastric acid secretion inhibitors and two types of antibiotics (amoxicillin and clarithromycin) for 14 days. The treatment success rate is 70% to 80%, but some patients discontinue medication on their own, often leading to treatment failure. In these patients, treatment difficulties may occur due to resistant strains.

[0007] Among the pathogenic factors of Helicobacter pylori, urease neutralizes gastric acid, thereby allowing Helicobacter pylori to settle and proliferate in a highly acidic environment. Furthermore, ammonia produced by enzymatic action affects gastric epithelial cells, and various cytokines produced when Helicobacter pylori stimulates gastric epithelial cells play a role in recruiting various inflammatory cells.

[0008] Therefore, it is necessary to develop a new therapeutic agent that can directly exert antibacterial effects or urease inhibitory effects on Helicobacter pylori.

[0009] [Related Technical Documents]

[0010] [Patent Documents]

[0011] (Patent Document 1) Korean Patent Publication No. 10-2000-0005291 Summary of the Invention

[0012] [Technical Problem]

[0013] The inventors have recognized the need for research and development of new therapeutic agents capable of exerting direct antibacterial or urease-inhibiting effects against Helicobacter pylori. Therefore, the object of the present invention is to provide a composition for bacterial eradication, comprising zaltaprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof, wherein the composition exhibits therapeutic effects on gastroesophageal reflux disease and / or peptic ulcers regardless of Helicobacter pylori infection, and is particularly effective in patients infected with Helicobacter pylori.

[0014] [Technical Solution]

[0015] To achieve the above object, the present invention discloses the following means.

[0016] In one aspect, the present invention provides a composition for Helicobacter pylori eradication comprising zataprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof.

[0017] [Beneficial Effects]

[0018] The composition for bacterial eradication of the present invention comprises zataprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof, and has the advantage that, due to its own Helicobacter pylori eradication action, the composition exhibits therapeutic effects on gastroesophageal reflux disease and / or peptic ulcers regardless of Helicobacter pylori infection, and particularly shows high efficacy in patients infected with Helicobacter pylori.

[0019] Furthermore, the composition for bacterial eradication of the present invention has the advantage that, in the assessment of all symptoms (heartburn, acid reflux, heartburn / acid reflux) arising from Helicobacter pylori infection, all symptoms tend to improve within 24 hours and last for 7 days.

[0020] The effects of the present invention are not limited to the above-described effects, and various effects may be included within the scope that will be obvious to those skilled in the art from the following description. Detailed Description

[0021] [Best Mode]

[0022] The present invention will be described in more detail below.

[0023] Specific explanations are as follows. The terms used herein are selected from the most widely used general terms that may be used in consideration of the function in the present invention, but they may vary depending on the intent of those skilled in the art, precedent, the emergence of new technologies, etc. Furthermore, in some cases, there are terms arbitrarily chosen by the applicant, and in such cases, their meaning will be described in detail in the corresponding part of the detailed description of the invention. Therefore, the terms used herein should be defined based on the meaning of the terms and the entirety of the invention, rather than simply based on the name of the terms.

[0024] Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms (such as those defined in commonly used dictionaries) should be interpreted as having a meaning consistent with their meaning in the context of the relevant field and not interpreted in an idealized or overly formal sense, unless expressly so defined in this invention.

[0025] Numerical ranges include the values ​​defined therein. Each maximum numerical limit given throughout this specification includes each lower numerical limit as expressly stated. Each minimum numerical limit given throughout this specification includes each higher numerical limit as expressly stated. Each numerical limit given throughout this specification will include each better numerical range within a wider numerical range as expressly stated.

[0026] In the following, each description and embodiment disclosed in this invention may also be applied to other descriptions and embodiments, respectively. In other words, all combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention should not be considered as limited by the specific descriptions described below.

[0027] As used herein, expressions such as “comprising” should be understood to imply the possibility of including other embodiments. This is an open-ended term, unless otherwise specifically stated in the phrase or sentence that includes the expression.

[0028] The term “zataprazan” as used herein may refer to zataprazan, its pharmaceutically acceptable salt, its hydrate or solvate, or mixtures thereof.Therefore, as used herein, "compositions comprising zataprazan" may refer to compositions comprising zataprazan, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof.

[0029] The present invention will be described in detail below.

[0030] Compositions for Helicobacter pylori eradication comprising zataprazan

[0031] The present invention discloses compositions for Helicobacter pylori eradication comprising zataprazan.

[0032] Specifically, the present invention provides a composition for Helicobacter pylori eradication comprising zataprazan, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof.

[0033] The composition for bacterial eradication of the present invention comprises zataprazan, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof, and has the advantage that, due to its own Helicobacter pylori eradication action, the composition exhibits therapeutic effects on gastroesophageal reflux disease and / or peptic ulcers regardless of Helicobacter pylori infection, and particularly shows high efficacy in patients infected with Helicobacter pylori.

[0034] Furthermore, the composition for bacterial eradication of the present invention exhibits superior efficacy in patients with Helicobacter pylori infection, particularly those with gastroesophageal reflux disease or peptic ulcers, due to the unique reversible proton pump inhibition effect of zataprazan, in both Helicobacter pylori eradication and gastric acid secretion inhibition (potassium-competitive acid blocker; P-CAB).

[0035] Furthermore, the composition for bacterial eradication of the present invention has the advantage that, in the assessment of all symptoms (heartburn, acid reflux, heartburn / acid reflux) arising from Helicobacter pylori infection, all symptoms tend to improve within 24 hours and persist for 7 days.

[0036] In the present invention, zataprazan is an example of an imidazo[1,2-a]pyridine derivative, and its chemical name is azirmonobutane-1-yl-[8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl] methyl ketone.

[0037] In this invention, zataprazan is the active ingredient for the eradication of Helicobacter pylori.

[0038] As used herein, the term "active ingredient" means a substance or group of substances that is intended to directly or indirectly express the efficacy and effects of a pharmaceutical composition through intrinsic pharmacological action, and includes a principal component.

[0039] The zataprazan of the present invention can be present in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed from a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" means any organic or inorganic acid addition salt having a concentration of zataprazan that is relatively non-toxic and harmless to the patient, and whose side effects do not diminish the beneficial efficacy of zataprazan.Organic and inorganic acids can be used as free acids. Inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, or tartaric acid can be used, 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, glutamate, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid can be used.

[0040] Unless otherwise specified, pharmaceutically acceptable salts of the present invention include acidic or basic salts that may be present in zataprazan. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of the hydroxyl group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (toluenesulfonate), etc., and may be prepared by methods known in the art for preparing salts.

[0041] Specifically, a pharmaceutically acceptable salt of zataprazan may be zataprazan citrate (azacyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methyl ketone citrate), but is not limited thereto.

[0042] As used herein, the term "hydrate" refers to a hydrate formed by binding the active ingredient, zataprazan, or a pharmaceutical salt thereof to water by non-covalent intermolecular forces, and it contains stoichiometric or non-stoichiometric amounts of water. Specifically, based on 1 mol of the active ingredient, the hydrate may contain a ratio of about 0.25 mol to about 10 mol of water, and more specifically, it may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, etc.

[0043] As used herein, the term "solvent" refers to a compound formed by binding the active ingredient, zataprazan, or a pharmaceutical salt thereof, and a solvent by non-covalent intermolecular forces, and it contains stoichiometric or non-stoichiometric amounts of solvent. Preferred solvents are volatile and non-toxic and can be administered to humans in very small amounts.Examples of such solvents 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. However, the solvates of the present invention are not limited to these examples, and specifically, based on 1 mol of active ingredient, the solvate may contain a solvent in a ratio of about 0.25 mol to about 10 mol, more specifically, it may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 3 mol, about 5 mol, etc.

[0044] The term "bacterial eradication" as used herein has a similar meaning to sterilization and refers to the elimination of bacteria. This term refers to a state in which metabolism ceases without directly killing the microorganism until the microorganism dies after a certain period of time, i.e., a state in which bacterial proliferation and growth cease. The eradication of Helicobacter pylori in this article can be considered as eliminating or eradicating Helicobacter pylori present in the human stomach, or stopping the proliferation and growth of Helicobacter pylori.

[0045] In this invention, the composition can be applied once to three times a day. Specifically, zatraprazan, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof can be applied once to three times a day for one week or more, or four weeks or more, and can be applied for 24 weeks or less, or 12 weeks or less. Specifically, the composition can be applied once to three times a day for one week to 24 weeks, two weeks to 24 weeks, four weeks to 24 weeks, one week to 12 weeks, two weeks to 12 weeks, or four weeks to 12 weeks, and preferably, the composition can be applied for four weeks to eight weeks, but is not limited thereto.

[0046] In this invention, zataprazan, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof may be contained in amounts from 1 mg to 100 mg, 2 mg to 60 mg or 3 mg to 40 mg of zataprazan (in the form of a free base). Specifically, zataprazan, its pharmaceutically acceptable salts, its hydrates or solvates, or mixtures thereof may be contained in amounts of about 3.3, 6.6, 13.1, 26.2 or 52.4 mg as zataprazan (in the form of a free base), and may be contained in amounts from 5 to 40 mg as zataprazan citrate, specifically 5 mg, 10 mg, 15 mg, 20 mg or 40 mg as zataprazan citrate, and more specifically 10 mg or 20 mg as zataprazan citrate.As described above, the compositions of the present invention, even when containing low doses (10 mg or 20 mg) of zataprazan, exhibit a Helicobacter pylori eradication effect equal to or greater than that of 40 mg Nexium tablets when administered once daily, thereby demonstrating a high cure rate and having the advantage of improving symptoms such as heartburn, acid reflux, and heartburn / acid reflux within 24 hours and 7 days of administration.

[0047] In the present invention, the compositions for bacterial eradication may include, but are not limited to, one or more pharmaceutical additives consisting of excipients, disintegrants, binders, and lubricants.

[0048] In the present invention, the excipients may be one or more of microcrystalline cellulose, lactose monohydrate, anhydrous lactose, sucrose, D-mannitol, starch, corn starch, or light anhydrous silica, but are not limited to.

[0049] In this invention, the disintegrant may include starch or modified starch such as sodium glycolate starch, corn starch, potato starch or pregelatinized starch; clay such as bentonite, montmorillonite or magnesium aluminum silicate; cellulose such as hydroxypropyl cellulose or carboxymethyl cellulose; alginate such as sodium alginate or alginic acid; crosslinked cellulose such as croscarmellose sodium; gum such as guar gum or xanthan gum; crosslinked polymers, such as copovidone; effervescent agents such as sodium bicarbonate or citric acid, etc. These may be used alone or in combination of two or more, but are not limited thereto.

[0050] In this invention, the adhesive may be one or more selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silica, mannitol, lactose, polyethylene glycol and mixtures thereof, but are not limited thereto.

[0051] In this invention, examples of lubricants may include calcium stearate, glyceryl monostearate, glyceryl palmitoyl stearate, magnesium stearate, sodium dodecyl sulfate, sodium stearoyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate, and talc. These may be used alone or in combination of two or more, but are not limited thereto.

[0052] In this invention, the composition for bacterial eradication may be a solid oral dosage form, but is not limited thereto.

[0053] In this invention, the solid oral dosage form may be one of tablets, film-coated tablets, capsules, powders, granules, pills, sugar tablets, oral gels, and oral dissolving film dosage forms, but is not limited thereto.

[0054] In particular, in the case of film-coated tablets, coating agents widely known in the art may be used, but are not limited thereto.

[0055] Pharmaceutical composition for the treatment of Helicobacter pylori containing zataprazan

[0056] The present invention provides a pharmaceutical composition for the treatment of Helicobacter pylori comprising zataprazan, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or a mixture thereof.

[0057] Zartrapazine is the same as described above.

[0058] The term "treatment" as used herein means the partial or complete relief, improvement, mitigation, inhibition, or delay of the onset of Helicobacter pylori, reduction of severity, or reduction of the occurrence of one or more symptoms or features by administration of the composition according to the invention.

[0059] The foregoing content regarding compositions for bacterial eradication can be applied to all therapeutic compositions, provided they are not contradictory.

[0060] Method for eradicating Helicobacter pylori, comprising administering a pharmaceutical composition to a subject in need

[0061] The present invention provides a method for eradicating Helicobacter pylori, comprising administering to a subject in need a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of zatrapazine, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof.

[0062] As used herein, the term “pharmaceutical effective amount” means the amount of composition that effectively eradicates Helicobacter pylori, for example, the amount of composition administered to a subject, which may include all amounts of the composition that prevent the occurrence or recurrence of Helicobacter pylori, relieve symptoms, inhibit direct or indirect pathological consequences, prevent metastasis, reduce the rate of progression, relieve or temporarily alleviate symptoms, or improve prognosis. In other words, pharmaceutically effective amount can be interpreted as including all doses of the composition that eradicate Helicobacter pylori.

[0063] Specifically, in the method for eradicating Helicobacter pylori according to the present invention, zataprazan (in the form of a free base) may be contained in amounts of 1 mg to 100 mg, 2 mg to 60 mg or 3 mg to 40 mg, specifically, zataprazan (in the form of a free base) may be contained in amounts of about 3.3, 6.6, 13.1, 26.2 or 52.4 mg of zataprazan (in the form of a free base) or in amounts of 5 to 40 mg of zataprazan citrate, specifically, 5 mg, 10 mg, 15 mg, 20 mg or 40 mg of zataprazan citrate, and more specifically, 10 mg or 20 mg of zataprazan citrate. Preferably, 5 to 40 mg of zataprazan citrate, more preferably 5 mg, 10 mg, 15 mg, 20 mg or 40 mg of zataprazan citrate, can be administered once daily to the subject to effectively treat the subject by eradicating Helicobacter pylori.

[0064] As used herein, the term “subject” means mammal, and specifically, mammals (including humans) include mammals such as humans, monkeys, cattle, horses, dogs, cats, rabbits, rats and mice, and more specifically, may refer to humans.Subjects may be infected or suspected of being infected with Helicobacter pylori due to causes such as gastroesophageal reflux disease, chronic gastritis, gastric or duodenal ulcers, and gastric cancer.

[0065] Here, the term "person infected with Helicobacter pylori" means a person who has been confirmed to be infected with Helicobacter pylori by breath or stool tests or upper endoscopy due to symptoms such as gastroesophageal reflux symptoms (heartburn, acid reflux, heartburn / acid reflux, etc.), upper abdominal pain, indigestion, or abdominal discomfort (a feeling of gas, bloating, or burning sensation). The term "person suspected of being infected with Helicobacter pylori" means a situation where the above symptoms are experienced.

[0066] The above description of compositions for bacterial eradication can be applied to all methods of bacterial eradication, provided that they are not contradictory.

[0067] Use in eradicating Helicobacter pylori

[0068] The present invention provides the use of compositions comprising zataprazan, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, or mixtures thereof in the eradication of Helicobacter pylori.

[0069] The foregoing description of compositions for bacterial eradication can be applied to all uses in bacterial eradication, provided that they are not contradictory.

[0070] Use in the preparation of medicaments for Helicobacter pylori eradication

[0071] The present invention provides the use of compositions comprising zaltaprazan, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, or mixtures thereof, in the preparation of medicaments for Helicobacter pylori eradication.

[0072] The compositions of the present invention used in the preparation of medicaments can be mixed with acceptable carriers, etc., and may further contain other reagents.

[0073] The foregoing description of compositions for bacterial eradication can be applied to all uses in the preparation of medicaments for Helicobacter pylori eradication, provided that they are not contradictory.

[0074] Hereinafter, the invention will be described in more detail using preparation examples and embodiments. It will be apparent to those skilled in the art that these preparation examples and examples are intended only to explain the invention more specifically, and the scope of the invention is not limited thereto.

[0075] The active ingredient used in the following preparation examples and embodiments is zastaprazan citrate salt, which is named zastaprazan or code name JP-1366 for convenience.

[0076] Preparation Examples

[0077] Preparation Example 1. Preparation of Zastaprazan Citrate

[0078] Azahexacyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone citrate was obtained according to the method described below. Specifically, zahexacyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone was obtained as described in Korean Patent Publication No. 10-1777971.The following describes the NMR analysis results of the aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone obtained above. 1H NMR (400 MHz, CDC13); 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). Instructions for Use, Page 6 / 20, CN 122295096 A

[0080] Next, the aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methyl ketone obtained above was mixed with an alcohol solvent (isopropanol, IPA), and the mixture was 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 prepared by dissolving citric acid (about 5 g) in acetone (about 33 g) was slowly added dropwise to the mixture over 60 minutes, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to approximately 20°C to 25°C and stirred for one hour. The resulting solid was filtered, washed with acetone, and dried under vacuum to obtain aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone citrate. The NMR analysis results of the obtained aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone citrate (zataprazan citrate) are described below. 1H 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=7.2 Hz, 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).

[0082] Preparation Example 2. Preparation of JP-1366 Capsules 5 mg (Zataprazan Citrate 5 mg)

[0083] 5 mg of aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methyl ketone citrate (zataprazan citrate) obtained according to Preparation Example 1 was mixed with 220.8 mg of D-mannitol, 13.0 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate to obtain a mixture. The mixture was filled into a hard capsule No. 1, which served as the bottom of the capsule, to prepare a capsule formulation.

[0084] The capsule formulation prepared in this manner is referred to as "JP-1366 Capsules 5 mg".

[0085] Preparation Example 3. Preparation of JP-1366 Tablets 20 mg (Zataprazan Citrate 20 mg)

[0086] 20 mg of aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methyl ketone citrate (zataprazan citrate) obtained according to Preparation 1 was mixed with 133.4 mg of microcrystalline cellulose, 6.4 mg of sodium stearoyl fumarate, 40.0 mg of anhydrous lactose, 6.0 mg of croscarmellose sodium, and 4.2 mg of magnesium stearate to obtain a mixture. The mixture was directly compressed to obtain tablets. Then, 8.0 mg of Opadry 03B54445 pink was used for coating to prepare film-coated tablets.

[0087] The film-coated tablets prepared in this way are called "JP-1366 Tablets 20 mg".

[0088] Preparation Example 4. Preparation of JP-1366 Capsules 20 mg (Zataprazan Citrate 20 mg)

[0089] 20 mg of aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methyl ketone citrate (zataprazan citrate) obtained according to Preparation Example 1 was mixed with 181.4 mg of D-mannitol, 12.4 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate to obtain a mixture. The mixture was filled into a hard capsule No. 1, which was used as the bottom of the capsule, to prepare a capsule formulation.

[0090] The capsule formulation prepared in this way is called "JP-1366 Capsules 20 mg".

[0091] Preparation Example 5. JP-1366 Capsules 20 mg Placebo

[0092] Zatraprazan Capsules 20 mg Placebo were prepared in the same manner as in Preparation Example 4, except that zatraprazan citrate, the main ingredient, was not used. The capsule formulation prepared in this manner is referred to as "JP-1366 Capsules 20 mg Placebo".

[0093] Example 1. In vitro efficacy test against Helicobacter pylori

[0094] Experiments were conducted to determine whether zaltaprazan had growth inhibition or urease activity inhibition effects against Helicobacter pylori under in vitro experimental conditions.

[0095] 1. Test material instructions 7 / 20 pages 9 CN 122295096 A

[0096] A. Drugs

[0097] Table 1 shows the drugs used in the in vitro experiments.

[0098] [Table 1]

[0099] B. Reagents

[0100] Table 2 shows the reagents used in the in vitro experiments.

[0101] [Table 2]

[0102] C. Bacterial strains

[0103] Helicobacter pylori (ATCC43504): The strain type used for antibiotic susceptibility testing according to the Clinical & Laboratory Standards Institute (CLSI) guidelines.

[0104] Helicobacter pylori 26695 (ATCC700329): A strain isolated from a UK patient known to be associated with the development of gastric cancer. This strain is positive for both cytotoxin-associated gene (CagA) and vacuole cytotoxin (VacA) and has a well-known genetic background, so it is primarily used for research purposes.

[0105] Helicobacter pylori SS1 (mouse colonizing strain): A strain known as the Sydney strain. The strain is positive for both CagA and VacA and has been confirmed to infect and colonize C57BL / 6 mice. This strain is used for animal testing.

[0106] D. Instruments

[0107] Table 3 shows the instruments used in the in vitro experiments.

[0108] [Table 3] Instruction manual 8 / 20 pages 10 CN 122295096 A

[0109] 2. Culture medium preparation

[0110] A. Culture medium

[0111] Liquid culture medium was prepared using Brain Heart Infusion (BHI; Difco Inc., Sparks, MD, USA), 7% differentiation medium (horse serum; Sigma CO., LTD., St. Louis, USA), and 0.4% isovitalex (BBL Inc., Sparks, MD, USA). Solid culture medium was prepared by adding 7% lysed horse blood (Oxoid Inc., Basingstoke, Hants, UK), 0.4% isovitalex, and 1.5%–2% Bacto-agar (Difco Inc., Sparks, MD, USA) to BHI.

[0112] B. Culture medium for measuring minimum inhibitory concentration (MIC)

[0113] Culture medium was prepared using Müller-Hinton broth (MH, Difco Inc., Sparks, MD, USA) [w / 7% differentiation medium (Sigma CO., LTD., St. Louis, USA), 0.4% isovitalex (BBL Inc., Sparks, MD, USA)].

[0114] 3. In vitro potency test - MIC and minimum bactericidal concentration (MBC) of zaltaprazan (JP-1366) against Helicobacter pylori

[0115] (1) Methods

[0116] Antibiotic susceptibility was tested using the microdilution method according to CLSI guidelines. Two-fold serial dilutions were performed in 12 steps in 48-well plates, with the highest concentration being 128 μg / mL for amoxicillin and clarithromycin, and 256 μg / mL for omeprazole. Bacteria were inoculated into wells containing only antibiotic-free medium to prepare a positive control group, and wells containing only antibiotic-free medium or inoculated bacteria were used as a negative control group. The concentration ranges of the test substances, zharaprazan (JP-1366) and fexuprazan, were determined through preliminary experiments. Helicobacter pylori stored in a freezer (-70°C or lower) was thawed, inoculated onto BHI agar (w / 7% lysed horse blood and 0.4% isovitalex), and cultured at 37°C under microaerobic conditions of 5% O2, 10% CO2, and 85% N2 gas for 3 days, then subcultured onto fresh medium. The cultured bacteria were harvested, suspended in PBS, and inoculated into each well at a concentration of 5 x 10⁵ cfu / mL, and then cultured at 37°C under microaerobic conditions of 5% O2, 10% CO2, and 85% N2 gas for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the MIC. Subsequently, 10 μL of culture solution of different concentrations from each well was spotted onto antibiotic-free BHI agar (w / 7% lysed horse blood and 0.4% isovitalex) and incubated for three days at 37°C under microaerobic conditions. The lowest concentration at which no bacterial growth occurred was determined as MBC.

[0117] (2) Experimental Results and Analysis

[0118] To determine the MIC, visual inspection was performed and absorbance was measured at 600 nm, and growth was confirmed based on the absorbance of the negative control group containing only culture medium. To determine the MBC, after the MIC was determined, 10 μL of culture solution from each well was spotted onto solid culture medium without antibiotics or test substances, and bacterial growth was examined.

[0119] Regarding the suitability of the system in this experiment, quality control was performed based on the MIC value of amoxicillin against Helicobacter pylori strain ATCC43504.Instructions 9 / 20 pages 11 CN 122295096 A

[0120] All tests were performed in duplicate, and the results were determined by performing experiments in triplicate.

[0121] Referring to Table 4 below, due to the low solubility of zataprazan (JP-1366), MIC analysis was difficult (poor solubility, formation of suspensions, interference in visual / absorbance analysis), so the inhibitory effect on Helicobacter pylori strains was confirmed by the MBC index.

[0122] The test substance zataprazan (JP-1366) was confirmed to have an inhibitory effect on three types of Helicobacter pylori strains that was at least 2 times better and up to 16 times better than omeprazole and non-surazine in terms of MBC.

[0123] [Table 4]

[0124] Example 2. Anti-Helicobacter pylori efficacy test in patients with erosive gastroesophageal reflux disease (Phase 2 clinical trial)

[0125] 1. Subject selection

[0126] Helicobacter pylori testing

[0127] Helicobacter pylori testing was performed by 13C-urea breath test (13C-UBT), gastroscopy (Campylobacter-like organism test, CLO) or tissue biopsy to confirm Helicobacter pylori positivity / negativity. Testing was performed at the screening visit (Visit 1) or randomized visit (Visit 2), and results from the same institution within 29 days prior to the randomized visit (Visit 2) could be substituted.

[0128] Inclusion criteria

[0129] Unless otherwise specified, subjects were required to meet all of the following inclusion criteria to participate in this clinical trial.

[0130] 1) Adult men and women aged 19 to 75 years from the date of written consent

[0131] 2) Those who experienced heartburn or acid reflux symptoms within 7 days prior to the screening visit (Visit 1)

[0132] [Table 5]

[0133] 3) Those who were diagnosed with grade A or higher erosive gastroesophageal reflux disease by upper gastrointestinal endoscopy at the same facility within 29 days prior to the randomized visit (Visit 2) according to the Los Angeles classification

[0134] [Table 6] Instructions 10 / 20 pages 12 CN 122295096 A

[0135] 4) Those who were able to complete the questionnaire and subject log

[0136] 5) Those who voluntarily consented to participate in the clinical trial in writing

[0137] Exclusion criteria

[0138] Those who met any of the following criteria were excluded from the clinical trial.

[0139] 1) Excluded diseases

[0140] (1) Barrett's esophagus longer than 3 cm or with significant structural abnormalities, as determined by upper gastrointestinal endoscopy during screening visits (visit 1)

[0141] (2) Eosinophilic esophagitis (which may include those that are negative on esophageal biopsy).

[0142] (3) Those with primary esophageal motility disorders or esophageal strictures

[0143] (4) Gastroesophageal varices

[0144] (5) Those with gastrointestinal bleeding or other abnormal bleeding as determined during screening visits (visits 1) by upper gastrointestinal endoscopy

[0145] (6) Those who have undergone gastric acid secretion suppression surgery or gastric or esophageal surgery. However, it may include those corresponding to the following.

[0146] ① Appendectomy, cholecystectomy, polyp removal

[0147] ② Endoscopic resection of malignant tumors or endoscopic resection of early gastric cancer (endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD)), which has healed and has not recurred for more than 5 years since the date of diagnosis

[0148] (7) Those with active duodenal ulcers, gastric ulcers or pancreatitis

[0149] (8) Zollinger-Ellison syndrome

[0150] (9) Those with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD)

[0151] (10) Those with warning symptoms (e.g., dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stools) that may be suspected of being a malignant disease of the gastrointestinal tract based on the investigator's judgment (however, this may include those that are found negative after confirmation of the presence of a tumor by upper gastrointestinal endoscopy).

[0152] 2) Medical history and comorbidities

[0153] (1) Those with clinically significant liver, kidney, nervous system, respiratory system, endocrine system, hematologic malignancy, cardiovascular system or urinary system disease

[0154] (2) Those with a history of malignancy within 5 years prior to the screening visit (Visit 1) (However, this may include those who have recovered from the date of diagnosis and have not relapsed for more than 5 years, but may exclude those with a history of malignancy of the digestive system and tumor resection (e.g., gastrectomy, colectomy, etc.), excluding cases falling into (1)-(6).)

[0155] (3) Those who have experienced alcohol or drug abuse within one year prior to the screening visit (Visit 1)

[0156] (4) Those with a confirmed history of human immunodeficiency virus (HIV)

[0157] (5) Those diagnosed with a mental illness that may affect the implementation of this clinical trial (e.g., schizophrenia, 11 / 20 pages, 13 CN 122295096) A disease, dementia)

[0158] 3) Laboratory test results (at the screening visit)

[0159] (1) Those with serum AST, ALT, ALP, γ-GT or total bilirubin levels exceeding twice the upper limit of normal

[0160] (2) Those with serum BUN or serum creatinine levels exceeding twice the upper limit of normal

[0161] (3) Active hepatitis B or hepatitis C (which may include those with no virus detected).

[0162] 4) Drug intake / treatment history

[0163] (1) Those who have taken drugs that are prohibited from being used concurrently or are expected to be taken during clinical trials.

[0164] 5) Allergy history

[0165] (1) Patients and their medical history of allergy to the clinical trial drug, Nexium tablets (esomeprazole) components, benzimidazole, penicillin antibiotics and macrolide antibiotics

[0166] 6) Other

[0167] (1) Pregnant women, breastfeeding women or women who tested positive in a pregnancy test or women with pregnancy potential or men who plan to become pregnant during this clinical trial

[0168] (2) Female partners of female subjects and male subjects with fertility potential who have not undergone infertility surgery and do not agree to use the following contraceptive methods during the clinical trial

[0169] (3) Those who have taken other clinical trial drugs within one month prior to the screening visit (visit 1)

[0170] (4) Those who, in addition to the above, are deemed unsuitable to participate in this clinical trial by the investigator

[0171] 2. Clinical trial method

[0172] This clinical trial is a randomized, double-blind, active-controlled, multicenter, phase 2 clinical trial targeting patients with erosive gastroesophageal reflux disease. Screening tests were conducted after subjects provided written consent to participate in the clinical trial. Subjects taking medications that might affect the gastric mucosa at the time of screening underwent an upper gastrointestinal endoscopy following a 2-week drug-free period (4 weeks for potassium-competitive acid blockers (P-CABs) or proton pump inhibitors (PPIs)). Subjects meeting the inclusion / exclusion criteria based on the screening test results were randomly assigned in a 1:1:1 ratio to test group 1, test group 2, or control group. Subjects were stratified by grades (A, B, C, D) according to the LA classification system based on upper gastrointestinal endoscopy. Randomized subjects, according to their assigned administration group, received the clinical trial drug once daily for four weeks. Four weeks after administration of the clinical trial drug, subjects visited the clinical trial facility for an upper gastrointestinal endoscopy to assess healing. Healed subjects underwent a safety follow-up (F / U) two weeks later, and unhealed subjects received the clinical trial drug for another four weeks (a total of 8 weeks of administration) and visited the clinical trial facility for an upper gastrointestinal endoscopy. Regardless of whether they have healed, perform a safe F / U after 2 weeks.

[0173] 3. Dosage, Administration Cycle and Method of Administration

[0174] A. Dosage

[0175] - Test Drug 1: JP-1366, 5 mg, 2 capsules (Zataprazan Citrate 10 mg)

[0176] - Test Drug 2: JP-1366, 20 mg, 1 capsule (Zataprazan Citrate 20 mg)

[0177] - Control Drug: Esomeprazole Magnesium Trihydrate 44.5 mg (Esomeprazole 40 mg, Nexium Tablet 40 mg 1 tablet)

[0178] B. Administration Cycle

[0179] Trial period per subject: up to 14 weeks

[0180] - Screening period: 15 days or 29 days

[0181] - Administration period: 4 weeks (or 8 weeks) Instructions for Use 12 / 20 pages 14 CN 122295096 A

[0182] - Safety F / U cycle: 2 weeks after the last administration of the clinical trial drug

[0183] C. Administration method

[0184] Subjects were given the clinical trial drug orally once daily at regular intervals on an empty stomach, according to their randomized administration groups, for four weeks (or eight weeks), starting from the day the clinical trial drug was provided.

[0185] An additional four-week administration period was administered only to subjects whose mucosal lesions had not healed after the four-week administration of the clinical trial drug.

[0186] 4. Efficacy Endpoints

[0187] A. Primary efficacy endpoint: Cumulative healing rate of mucosal lesions up to week 8 after administration of the clinical trial drug (%) Recovery of erosions of normal mucosa as observed during upper gastrointestinal endoscopy

[0188] B. Secondary efficacy endpoints: ① Mucosal lesion healing rate up to week 4 after administration of the clinical trial drug (%) ② Symptom evaluation via subject logs A. Evaluation of symptoms (heartburn, acid reflux, heartburn / acid reflux) within 24 hours after administration of the clinical trial drug B. Evaluation of symptoms (heartburn, acid reflux, heartburn / acid reflux) 7 days after administration of the clinical trial drug C. Number of days to achieve complete remission (CR, 7 days of heartburn disappearance and acid reflux) after administration of the clinical trial drug D. Proportion of symptom-free days (heartburn, acid reflux, heartburn / acid reflux) at weeks 4 and 8 after administration of the clinical trial drug (daytime, nighttime, daytime / nighttime) ③ Changes in the frequency and severity of major symptoms at weeks 4 and 8 of clinical trial drug administration compared to baseline on the Gastroesophageal Reflux Disease Questionnaire (RDQ) ④ Changes in total score at weeks 4 and 8 of clinical trial drug administration compared to baseline on the GERD Health Related Quality of Life (GERD-HRQL)

[0189] 5. Safety endpoints

[0190] (1) Adverse reactions

[0191] (2) Vital signs

[0192] (3) Laboratory tests

[0193] (4) Electrocardiogram (12-lead ECG)

[0194] (5) Physical examination

[0195] 6. Statistical analysis methods

[0196] A. Primary efficacy endpoint

[0197] Cumulative healing rate of mucosal lesions up to week 8 after administration of clinical trial drug (%)

[0198] The proportion of subjects in the administration group whose erosions recovered to normal mucosa from the initial administration of clinical trial drug up to week 8 and the 95% confidence intervals on both sides. To compare each test group with the control group (JP-1366 10 mg vs. Nexium tablets 40 mg, JP-1366 20 mg vs. Nexium tablets 40 mg), the Cochran-Mantel-Haenszel method, corrected for baseline LA grades (A, B, C, D) as stratification factors, was used to obtain the lower limit of each bilateral 95% confidence interval.

[0199] B. Secondary efficacy endpoints

[0200] ① Mucosal lesion healing rate up to week 4 after administration of the clinical trial drug (%) Instructions for use 13 / 20 pages 15 CN 122295096 A

[0201] The proportion of subjects in the administration group whose erosions recovered to normal mucosa from the initial administration of the clinical trial drug up to week 4, and bilateral 95% confidence intervals.To compare each test group with the control group (JP-1366 10 mg vs. Nexium tablets 40 mg, JP-1366 20 mg vs. Nexium tablets 40 mg), the Cochran-Mantel-Haenszel method, corrected for baseline LA grades (A, B, C, D) as stratification factors, was used to obtain the lower limit of each 95% confidence interval.

[0202] ② Symptom evaluation by subject logs

[0203] A. Evaluation of symptoms (heartburn, acid reflux, heartburn / acid reflux) within 24 hours after administration of the clinical trial drug: The mean evaluation of symptoms (heartburn, acid reflux, heartburn / acid reflux) in each test group and the control group within 24 hours after the first administration of the clinical trial drug was analyzed using an analysis of covariance (ANCOVA) model with baseline LA grades (A, B, C, D) as covariates.

[0204] B. Evaluation of symptoms (heartburn, acid reflux, heartburn / acid reflux) 7 days after administration of the clinical trial drug: The mean evaluation of symptoms (heartburn, acid reflux, heartburn / acid reflux) 7 days after the first administration of the clinical trial drug was analyzed in each test group compared with the control group using an ANCOVA model with baseline LA grades (A, B, C, D) as covariates.

[0205] C. Number of days to achieve CR (heartburn resolution and acid reflux for 7 days) after administration of the clinical trial drug: CR (heartburn resolution and acid reflux for 7 days) was defined as a symptom score of 0 for seven consecutive days after the first administration of the clinical trial drug, and this event was based on the first CR. When no CR was found, the case was considered censored. Kaplan-Meier curves and medians and their 95% confidence intervals were presented by the administration group, and the comparison of each test group with the control group was analyzed using a stratified log-rank test corrected for baseline LA grades as the stratification factor.

[0206] D. Proportion of asymptomatic days (heartburn, acid reflux, heartburn / acid reflux) (daytime, nighttime, daytime / nighttime) at 4 and 8 weeks after administration of the clinical trial drug: An ANCOVA model analysis with baseline LA grades (A, B, C, D) as covariates was used to compare the proportion of asymptomatic days (heartburn, acid reflux, heartburn, and acid reflux) at 4 and 8 weeks after the first administration of the clinical trial drug, respectively, between the test group and the control group.

[0207] ③ An ANCOVA model analysis with baseline LA grades (A, B, C, D) as covariates was used to compare the changes in the frequency and severity of major symptoms at weeks 4 and 8 after administration of the clinical trial drug, compared to the baseline gastroesophageal RDQ, between the test group and the control group. Changes in the final results were subjected to the same statistical analysis as described above, excluding baseline.

[0208] ④ An ANCOVA model with baseline LA grades (A, B, C, D) as covariates was used to analyze the changes in total scores at weeks 4 and 8 of clinical trial drug administration, comparing each test group with the control group against the baseline of the Quality of Life Assessment (GERD-HRQL). Changes in the final results were subjected to the same statistical analysis as described above, excluding baseline comparisons.

[0209] C. Safety Endpoints

[0210] For subjects who experienced at least one adverse reaction (or adverse drug reaction), the number and incidence of the reaction and their 95% confidence intervals were presented by the administration group, and a chi-square test or Fisher's exact test was performed to test whether there was a difference in the incidence of adverse reactions (or adverse drug reactions) between the control group and each test group. In addition, the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) was used to present data coded as System Organ Class (SOC) and Preferred Time (PT). Using the latest version of MedDRA, serious adverse reactions, adverse reactions leading to discontinuation of clinical trial drug administration, and adverse reactions causing death are also summarized as SOC and PT. For laboratory tests, vital signs, and electrocardiograms (12-lead ECG), descriptive statistics (number of subjects, mean, standard deviation, median, minimum, maximum), changes at each visit, and changes from baseline are presented as continuous data, and contingency tables are created for categorical data. For laboratory tests and ECGs (12-lead ECG), changes from baseline after administration of the clinical trial drug are summarized in a transformation table at each assessment time point, categorized as normal or clinically insignificant abnormalities (normal or abnormal NCS) and clinically significant abnormalities (abnormal CS). For physical examinations, a list is presented of subjects who were normal or clinically insignificant abnormalities (abnormal NCS) at baseline but became clinically significant abnormalities (abnormal CS) after administration of the clinical trial drug.

[0211] 7. Results of Phase II Clinical Trials

[0212] A. Confirmation of Symptom Improvement

[0213] In the assessment of all symptoms (heartburn, acid reflux, heartburn / acid reflux) within 24 hours and 7 days after administration of the clinical trial drugs, it was confirmed that all symptoms tended to improve within 24 hours and 7 days after administration of investigational drugs 1 and 2, which were clinical trial drugs.

[0214] B. Confirmation of Healing Rate

[0215] (1) Helicobacter pylori Positive Group (Infection Group)

[0216] The JP-1366 20 mg (Zataprazan 20 mg) administration group showed 100% healing effect at weeks 4 and 8, but Nexium 40 mg showed an effect of 87.5% (see Table 7).

[0217] [Table 7]

[0218] (2) Helicobacter pylori Negative Group

[0219] The JP-1366 20 mg (Zataprazan 20 mg) administration group showed the same effect as Nexium 40 mg (see Table 8). Thus, it is clinically confirmed that Zataprazan can show the same effect as the control group Nexium 40 mg, even at significantly low doses.

[0220] [Table 8]

[0221] (3) Overall healing rate

[0222] Taking into account the results of the Helicobacter pylori positive group (infection group) and the Helicobacter pylori negative group, in terms of overall healing rate, the percentage of subjects whose mucosal lesions were completely healed at week 4 after administration of the clinical trial drug in the JP-1366 10 mg group was 93.75% (45 / 48 people), in the JP-1366 20 mg group it was 91.49% (43 / 47 people), and in the esomeprazole 40 mg group it was 89.80% (44 / 49 people).

[0223] (4) Conclusion

[0224] Nexium 40 mg showed a higher erosion healing rate in Helicobacter pylori-negative patients compared with Helicobacter pylori-positive patients, but the pharmaceutical composition according to the invention showed therapeutic effects on gastroesophageal reflux disease and / or peptic ulcers regardless of Helicobacter pylori infection, and on the contrary, it showed a trend of showing higher efficacy in patients infected with Helicobacter pylori. This is due to the bacterial eradication effect of zataprazan itself contained in the pharmaceutical composition according to the invention.

[0225] Example 3. Anti-Helicobacter pylori efficacy test in patients with erosive gastroesophageal reflux disease (Phase 3 clinical trial)

[0226] 1. Subject selection

[0227] Helicobacter pylori test

[0228] Helicobacter pylori test was performed by 13C-UBT, gastroscopy (Campylobacter-like organism test, CLO) or tissue biopsy to confirm Helicobacter pylori positivity / negativity. Tests were conducted at either the screening visit (Visit 1) or the randomized visit (Visit 2), and results from the same institution within 29 days prior to the randomized visit (Visit 2) could be substituted.

[0229] Inclusion Criteria

[0230] Unless otherwise specified, subjects were required to meet all of the following inclusion criteria to participate in this clinical trial.

[0231] 1. Adult men and women aged 19 years or older as of the date of written consent

[0232] 2. Those who have experienced heartburn or acid reflux symptoms within 7 days prior to the screening visit and whose symptoms are of the severity and frequency corresponding to either of the following 1) or 2): 1) Those who have experienced mild or more severe heartburn or acid reflux twice or more per week 2) Those who have experienced moderate or more severe heartburn or acid reflux once or more per week 3. Those who have been diagnosed with grade A or higher erosive gastroesophageal reflux disease by endoscopy within 15 days prior to randomization according to the Los Angeles Classification† [Table 9]

[0233] 4. Those who have fully understood the clinical trial and have voluntarily given written consent to participate in the clinical trial

[0234] Exclusion Criteria 16 / 20 pages 18 CN 122295096 A

[0235] Those who meet any of the following criteria are excluded from this clinical trial.

[0236] Subjects must not meet any of the following criteria.

[0237] 1. Individuals who cannot undergo endoscopy

[0238] 2. Medical history

[0239] 1) Those with warning symptoms (e.g., dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stools) that may be suspected of being a gastrointestinal malignancy (however, those who test negative after confirming the presence of a malignancy by endoscopy may be excluded).

[0240] 2) Patients with eosinophilic esophagitis (those who test negative on esophageal biopsy may be excluded).

[0241] 3) Those with endoscopically confirmed gastroesophageal stricture, gastroesophageal varices, Barrett's esophagus, active peptic ulcer, gastrointestinal bleeding, or gastrointestinal malignancies.

[0242] 4) Patients with Zollinger-Ellison syndrome.

[0243] 5) Those with or suspected of having a history of primary esophageal motility disorder, IBS, or IBD (including pancreatitis) within the past 3 months.

[0244] 6) Those who have undergone gastric acid secretion suppression surgery or gastric or esophageal surgery (however, those with a history of appendectomy, cholecystectomy, and polypectomy may be excluded).

[0245] 7) Those with clinically significant diseases such as liver, kidney, cardiovascular, respiratory, endocrine, urinary, neuropsychiatric, and hematologic disorders.

[0246] 8) Those with a history of malignancy within five years prior to the screening time (however, those with a history of malignancy in the digestive system are excluded regardless of the period).

[0247] 3. Those who exhibit the following abnormalities in laboratory tests performed during screening laboratory tests: 1) ALT or AST > 2.0 x ULN 2) Total bilirubin > 2.0 x ULN 3) ALP or GGT > 2.0 x ULN 4) eGFR R < 70 mL / min / 1.73 m2 (Chicken Kidney Disease Epidemiology Collaboration (CKD-EPI) equation) 5) Positive results in serum tests (HBsAg, HCV Ab, HIV Ab, syphilis harvester protein test) 6) Those who show clinically significant abnormal findings in electrocardiogram 4. Allergies and drug hypersensitivity 1) Those who are known to have hypersensitivity to components or additives of the clinical trial drug 2) Those who have a clinically significant allergic disease (excluding mild allergic rhinitis that does not require administration) or a history of allergy to other drugs (aspirin, antibiotics, etc.).

[0248] 5. Control Drugs and Treatments

[0249] 1) Those who took acid secretion inhibitors such as P-CAB or PPIs within two weeks prior to endoscopy at the time of screening

[0250] 2) Those who took reflux esophagitis-related medications (antacids, prokinetic agents, histamine-2 receptor antagonists) two or more times within one week prior to endoscopy at the time of screening

[0251] 3) Those who could not discontinue medications that may cause ulceration during the clinical trial period, such as aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs)

[0252] 4) Those who were taking or needed to take medications that were contraindicated for this clinical trial. However, those taking contraindicated medications may participate after a two-week washout period. When the period corresponding to 5 times the half-life of the contraindicated drug (page 17 / 20, CN 122295096 A) exceeds two weeks, the washout period should be 5 times the half-life of the drug.

[0253] 6. Pregnant and lactating women

[0254] 7. Subjects and their spouses (or partners) who do not use medically acceptable methods of contraception throughout the clinical trial

[0255] 1) Use of intrauterine devices with a proven rate of pregnancy failure

[0256] 2) Use of double-barrier methods of contraception (male condoms and occluders, diaphragms or neck caps) and concurrent use of spermicides

[0257] 3) Infertility surgery (vasectomy, tubal ligation, hysterectomy)

[0258] 8. Those with a clinically significant history of mental illness, drug or alcohol abuse

[0259] 9. Other than the above, persons deemed unsuitable by the investigator to participate in this clinical trial

[0260] 2. Clinical Trial Methods

[0261] Persons who voluntarily consent to participate in this clinical trial are screened through screening visits, and only eligible subjects are allowed to participate in this clinical trial based on inclusion / exclusion criteria.Eligible participants were randomly assigned to either the test or control group and received the clinical trial drug at baseline visit (V2) according to their assigned group. Visits were conducted on day 1 and week 4 during the total four-week treatment period, with the clinical trial drug administered orally once daily.

[0262] 3. Dosage, Administration Cycle, and Administration Method

[0263] A. Dosage

[0264] - Test drug: JP-1366 20 mg 1 capsule (Zataprazan citrate 20 mg)

[0265] - Control drug: Esomeprazole magnesium trihydrate 44.5 mg (Esomeprazole 40 mg, Nexium tablet 40 mg 1 tablet)

[0266] B. Administration Cycle

[0267] Approximately 12 weeks (±14 days)

[0268] 1. Screening period: Up to two weeks from the first administration of the clinical trial drug

[0269] 2. Treatment period: Four weeks (±7 days) after the first administration of the clinical trial drug

[0270] 3. Follow-up: Two weeks (±14 days) after the last administration of the clinical trial drug

[0271] C. Administration Method

[0272] –According to the randomly assigned administration group, the clinical trial drug was administered orally once daily for a total of four weeks, at the set time each day, regardless of diet.

[0273] [Table 10]

[0274] 4. Concomitant medications

[0275] A. Contraindicated concomitant medications

[0276] The following drugs are contraindicated during this clinical trial.

[0277] 1. All gastric acid secretion inhibitors other than clinical trial drugs, 18 / 20 pages, 20 CN 122295096 A

[0278] 2. Gastric mucosal protectants

[0279] 3. Antacids

[0280] 4. Motility promoters

[0281] 5. Other gastrointestinal drugs

[0282] 6. Steroid preparations (however, topical, epidural and inhalation administration are permitted.)

[0283] 7. NSAIDs (however, investigators may permit the short-term use of NSAIDs for the purpose of treating acute pain.)

[0284] 8. Cholinergic drugs, antipsychotics, antithrombotic drugs (anticoagulants or antiplatelet agents (including aspirin))

[0285] 9. Drugs known to interact with clinical trial drugs

[0286] B. Concomitant medications

[0287] 1 1. Medications for the treatment of comorbidities may be used without changes in administration method and dosage. However, changes in administration and dosage are possible when it is determined that medications administered for the treatment of comorbidities do not affect this clinical trial. Other medications may be administered concurrently when they are determined not to affect this clinical trial.

[0288] 2. Medications may be permitted for use in the pretreatment of endoscopy and UBT.

[0289] 5. Results of Phase III Clinical Trials

[0290] A. Confirmation of Mucosal Damage Healing Rate

[0291] (1) Confirmation of Cumulative Healing Rate of Mucosal Damage in Subjects Tested Positive for Helicobacter pylori

[0292] The cumulative healing rate of mucosal damage based on the presence or absence of Helicobacter pylori infection refers to the proportion of subjects whose mucosal damage was healed 4 weeks after administration of the clinical trial drug during endoscopy.

[0293] Based on the presence or absence of Helicobacter pylori infection, the frequency and percentage of mucosal damage at week 4 after administration of the clinical trial drug were presented by the administration group. Differences between the administration groups (test group - control group) were analyzed using the Cochran-Mantel-Haenszel method corrected for baseline LA classification as a stratification factor, and 95% confidence intervals for these differences were presented.

[0294] Per Protocol Set (PPS)

[0295] As the primary analysis group of this clinical trial, the number of subjects testing positive for Helicobacter pylori was 26 in the test group and 22 in the control group. The proportion of subjects whose mucosal lesions were healed during endoscopy at week 4 after administration of the clinical trial drug was 100.00% (26 / 26 subjects) in the test group and 81.82% (18 / 22 subjects) in the control group, showing a statistically significant difference between the two administration groups (p = 0.0214).

[0296] Full Analysis Set (FAS)

[0297] According to the FAS analysis results, the number of subjects testing positive for Helicobacter pylori was 28 in the test group and 25 in the control group. At week 4 after administration of the clinical trial drug, the percentage of subjects whose mucosal lesions healed during endoscopy was 96.43% (27 / 28 subjects) in the test group and 80.00% (20 / 25 subjects) in the control group. At week 4, the test group showed significantly superior results compared to the control group.

[0298] [Table 11]

[0299] [Table 12] Specification 19 / 20 pages 21 CN 122295096 A

[0300] While specific portions of the invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the invention is not limited thereto. Therefore, the actual scope of the invention will be defined by the appended claims and their equivalents. Specification 20 / 20 pages 22 CN 122295096 A.

Claims

1. A treatment for Helicobacter pylori ( Helicobacter pylori An eradication composition comprising zaltaprazan, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof.

2. The composition for Helicobacter pylori eradication according to claim 1, wherein the pharmaceutically acceptable salt of zataprazan is zataprazan citrate.

3. The composition for Helicobacter pylori eradication according to claim 1, wherein the composition for eradication comprises a pharmaceutically acceptable salt of zataprazan in an amount of 10 mg, 20 mg or 40 mg.

4. The composition for Helicobacter pylori eradication according to claim 1, wherein the composition for eradication is applied once to three times daily.

5. The composition for Helicobacter pylori eradication according to claim 1, wherein the composition for eradication is applied once daily.

6. The composition for Helicobacter pylori eradication according to claim 1, wherein the composition for eradication is formulated as a solid oral preparation.

7. The composition for Helicobacter pylori eradication according to claim 6, wherein the solid oral formulation is any one of tablets, film-coated tablets, capsules, powders, granules, pills, lozenges, oral gels, and oral dissolving film formulations.

8. A treatment for Helicobacter pylori ( H. pylori A therapeutic composition comprising zattaprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate thereof, or a mixture thereof.

9. A method for eradicating Helicobacter pylori, the method comprising administering to a subject in need of it a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of zatraprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof.

10. Use of a composition in the eradication of Helicobacter pylori, said composition comprising zaltaprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof.

11. Use of a composition in the preparation of a medicament for the eradication of Helicobacter pylori, the composition comprising zaltaprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvate, or a mixture thereof.