КОМПОЗИЦИЯ ДЛЯ УНИЧТОЖЕНИЯ HELICOBACTER PYLORI, СОДЕРЖАЩАЯ ЗАСТАПРАЗАН ИЛИ ЕГО ФАРМАЦЕВТИЧЕСКИ ПРИЕМЛЕМУЮ СОЛЬ

Abstract

Раскрыта композиция для уничтожения Helicobacter pylori, содержащая застапразан или его фармацевтически приемлемую соль.

Description

Composition for eradicating Helicobacter pylori comprising zastaprazan or a pharmaceutically acceptable salt thereof

[0001] The present invention relates to a composition for eradicating Helicobacter pylori, comprising zastaprazan or a pharmaceutically acceptable salt thereof, and more specifically, to a composition for eradicating Helicobacter pylori, which exhibits a therapeutic effect on gastroesophageal reflux disease and / or peptic ulcer regardless of Helicobacter pylori (H. pylori) infection due to its own eradication effect, and rather, exhibits a tendency to exhibit a high effect in patients infected with Helicobacter pylori (H. pylori).

[0002] Helicobacter pylori (H. pylori) is a gram-negative spiral bacterium that lives in the human gastric mucosa. It is classified as a group 1 carcinogen by the World Health Organization (WHO) and is a bacterium that is infected with about half of the adults in Korea. Helicobacter pylori (H. pylori) is a bacterium that parasitizes the gastric mucosa and continues to multiply, and is a bacterium that does not disappear on its own unless appropriate treatment is received.

[0003] The infection route of Helicobacter pylori (H. pylori) is not yet clearly known, but it is known to be transmitted from person to person. It is understood to be closely related to the unique lifestyle of Koreans, which exposes them to the risk of infection by Helicobacter pylori (H. pylori).

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

[0005] A multicenter study of asymptomatic adults in Korea showed a serological prevalence rate of 51.0% in 2015, a steady decrease compared to the past. This can be attributed to not only active treatment but also improved economic status and sanitary conditions.

[0006] Primary eradication of Helicobacter pylori (H. pylori) involves taking a proton pump inhibitor and two antibiotics (amoxicillin and clarithromycin) for 14 days. The treatment success rate is 70-80%, but some patients discontinue medication arbitrarily, leading to treatment failure. These patients may face treatment difficulties due to resistant strains.

[0007] Among the pathogenic factors of Helicobacter pylori (H. pylori), urease not only neutralizes gastric acid and allows H. pylori to settle and proliferate in a strongly acidic environment, but also the ammonia produced as a result of the enzymatic action affects gastric epithelial cells, and various cytokines produced when H. pylori stimulates gastric epithelial cells play a role in recruiting various inflammatory cells.

[0008] Therefore, it can be seen that there is a need to develop a new treatment that can directly exert antibacterial or urease inhibitory effects against Helicobacter pylori (H. pylori).

[0009] [Prior Art Literature]

[0010] [Patent Document]

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

[0012] The inventors of the present invention have identified the need for research and development of a new therapeutic agent capable of exerting a direct antibacterial effect or urease inhibitory effect against Helicobacter pylori (H. pylori). Accordingly, the present invention aims to provide an eradication composition that exhibits a therapeutic effect on gastroesophageal reflux disease and / or peptic ulcer regardless of Helicobacter pylori (H. pylori) infection, and in particular, exhibits a high effect in patients infected with Helicobacter pylori (H. pylori) using zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0013] In order to achieve the above purpose, the present invention discloses the following means.

[0014] In one aspect, the present invention discloses a composition for eradicating Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0015] The sterilizing composition of the present invention comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and exhibits a therapeutic effect on gastroesophageal reflux disease and / or peptic ulcer regardless of the presence or absence of Helicobacter pylori (H. pylori) infection due to the sterilizing effect of zastaprazan itself on Helicobacter pylori (H. pylori), and has the advantage of exhibiting a particularly high effect on patients infected with Helicobacter pylori (H. pylori).

[0016] In addition, the sterilizing composition of the present invention has the advantage of showing a tendency for all symptoms (heartburn, acid reflux, heartburn / acid reflux) to improve within 24 hours and for 7 days in an evaluation of all symptoms (heartburn, acid reflux, heartburn / acid reflux) caused by Helicobacter pylori (H. pylori) infection.

[0017] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0018] Hereinafter, the present specification will be described in more detail.

[0019] 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.

[0020] 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.

[0021] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] Hereinafter, the present invention will be described in detail.

[0026] Composition for eradicating Helicobacter pylori containing zastaprazan

[0027] The present invention discloses a composition for eradicating Helicobacter pylori comprising zastaprazan.

[0028] Specifically, the present invention provides a composition for eradicating Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0029] The sterilizing composition of the present invention comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and exhibits a therapeutic effect on gastroesophageal reflux disease and / or peptic ulcer regardless of the presence or absence of Helicobacter pylori (H. pylori) infection due to the sterilizing effect of zastaprazan itself on Helicobacter pylori (H. pylori), and has the advantage of exhibiting a particularly high effect on patients infected with Helicobacter pylori (H. pylori).

[0030] In addition, the sterilizing composition of the present invention exhibits a synergistic effect of the gastric acid secretion inhibitory effect (potassium competitive gastric acid secretion inhibitor; P-CAB) due to the unique reversible proton pump inhibitory effect of zastaprazan and the Helicobacter pylori sterilization effect, thereby exhibiting a higher therapeutic effect in patients with gastroesophageal reflux disease or peptic ulcer infected with Helicobacter pylori.

[0031] In addition, the sterilizing composition of the present invention has the advantage of showing a tendency for all symptoms (heartburn, acid reflux, heartburn / acid reflux) to improve within 24 hours and for 7 days in an evaluation of all symptoms (heartburn, acid reflux, heartburn / acid reflux) caused by Helicobacter pylori (H. pylori) infection.

[0032] 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.

[0033] In the present invention, zastaprazan is an active ingredient for eradicating Helicobacter pylori (H. pylori).

[0034] 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 the main ingredient.

[0035] 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.

[0036] Pharmaceutically acceptable salts of the present invention include acidic or basic salts that may be present in zastaprazan, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of the hydroxy 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 (tosylate) salts, and may be prepared by methods known in the art for preparing salts.

[0037] 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).

[0038] 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.

[0039] 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 the solvent 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.

[0040] In the present invention, the term "sterilization" has a similar meaning to sterilization, and means removing bacteria. It refers to a state in which the metabolism of microorganisms is stopped without directly killing them, and they die after a certain period of time, that is, a state in which the growth and development of bacteria are stopped. In the present invention, the eradication of Helicobacter pylori (H. pylori) can be considered to include the removal or eradication of Helicobacter pylori (H. pylori) existing in the human stomach, or the stopping of the growth and development of Helicobacter pylori (H. pylori).

[0041] In the present invention, the composition may be administered once a day to three times a day. Specifically, the zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be administered once a day to three times a day for at least one week or at least four weeks, and may be administered for up to 24 weeks and up to 12 weeks. Specifically, the composition may be administered once a day to three times a day for 1 week to 24 weeks, 2 weeks to 24 weeks, 4 weeks to 24 weeks, 1 week to 12 weeks, 2 weeks to 12 weeks, or 4 weeks to 12 weeks, and preferably, may be administered for 4 weeks to 8 weeks, but is not limited thereto.

[0042] In the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be included 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 included 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 or 20 mg as zastaprazan citrate salt. In this way, the composition of the present invention, even if it contains a low dose (10 mg or 20 mg) of zastaprazan, is administered once a day and exhibits an effect of eradicating Helicobacter pylori (H. pylori) equivalent to or greater than that of Nexium tablet 40 mg, thereby exhibiting a high cure rate, and has the advantage of improving symptoms such as heartburn, acid reflux, and heartburn / acid reflux within 24 hours and for 7 days after administration.

[0043] In the present invention, the sterilizing composition may include one or more pharmaceutical additives composed of an excipient, a disintegrant, a binder, and a lubricant, but is not limited thereto.

[0044] 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.

[0045] 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, but are not limited thereto.

[0046] 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.

[0047] 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.

[0048] In the present invention, the sterilizing composition may be a solid oral preparation, but is not limited thereto.

[0049] 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.

[0050] In particular, in the case of film-coated tablets, coating agents widely known in the art can be used, but are not limited thereto.

[0051] Pharmaceutical composition for the treatment of Helicobacter pylori containing zastaprazan

[0052] The present invention provides a pharmaceutical composition for treating Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0053] The above Jastaprajan is as discussed above.

[0054] In the present invention, the term “treatment” means partially or completely alleviating, improving, alleviating, inhibiting or delaying the onset of Helicobacter pylori, reducing the severity or reducing the occurrence of one or more symptoms or characteristics by administering a composition according to the present invention.

[0055] The contents of the sterilizing composition described above can be applied to all of the above therapeutic compositions as long as they are not contradictory.

[0056] A method for eradicating Helicobacter pylori, comprising administering a pharmaceutical composition to a subject in need thereof.

[0057] The present invention provides a method for eradicating Helicobacter pylori, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0058] The term "pharmaceutically effective amount" in the present invention refers to an amount effective for eradicating Helicobacter pylori, for example, an amount of a composition administered to a subject, which may include all amounts of the composition that prevent the occurrence or recurrence of Helicobacter pylori, alleviate symptoms, inhibit direct or indirect pathological consequences, prevent metastasis, reduce the rate of progression, alleviate or temporarily alleviate a condition, or improve the prognosis. In other words, the pharmaceutically effective amount may be interpreted to encompass all doses at which Helicobacter pylori can be eradicated by the composition.

[0059] Specifically, in the method for eradicating Helicobacter pylori according to the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be included in an amount of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg as zastaprazan (free base form), specifically about 3.3, 6.6, 13.1, 26.2, or 52.4 mg as zastaprazan (free base form), and 5 to 40 mg as zastaprazan citrate salt, specifically 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg as zastaprazan citrate salt, and more specifically 10 mg or 20 mg as zastaprazan citrate salt. Preferably, zastaprazan citrate salt is administered to the subject once a day in an amount of 5 to 40 mg, more preferably 5 mg, 10 mg, 15 mg, 20 mg or 40 mg, to eradicate Helicobacter pylori and effectively treat the subject.

[0060] 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 infected with Helicobacter pylori or suspected of being infected due to gastroesophageal reflux disease, chronic gastritis, stomach or duodenal ulcers, gastric cancer, etc.

[0061] Here, “a person infected with Helicobacter pylori” refers to a person who has been confirmed to be infected with Helicobacter pylori through a breath or stool test or upper endoscopy due to symptoms such as gastroesophageal reflux symptoms (heartburn, acid reflux, heartburn / acid reflux, etc.), upper abdominal pain, indigestion, and abdominal discomfort (a feeling of fullness of gas, bloating, or burning sensation). “A person suspected of being infected with Helicobacter pylori” refers to a case where the person experiences the above symptoms.

[0062] The contents of the sterilizing composition described above can be applied to all of the above sterilizing methods as long as they are not contradictory to each other.

[0063] For the purpose of eradicating Helicobacter pylori

[0064] The present invention provides the use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof for eradicating Helicobacter pylori.

[0065] The contents of the sterilizing composition described above can be applied to all uses for sterilizing Helicobacter pylori, unless they are contradictory to each other.

[0066] Use for the manufacture of a drug for eradicating Helicobacter pylori

[0067] The present invention provides a use for the manufacture of a medicament for eradicating Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0068] 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.

[0069] The contents of the sterilizing composition described above can be applied to all uses for the manufacture of the above Helicobacter pylori sterilizing agent, as long as they are not contradictory to each other.

[0070] Hereinafter, the present invention will be described in more detail using manufacturing examples and examples. It will be apparent to those skilled in the art that these manufacturing examples and examples are intended solely to illustrate the present invention more specifically and that the scope of the present invention is not limited by them.

[0071] 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.

[0072] Manufacturing example.

[0073] Manufacturing Example 1. Manufacturing of zastaprazan citrate salt

[0074] 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.

[0075] 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).

[0076] 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.

[0077] 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=7.2Hz, 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)

[0078] Manufacturing Example 2. Manufacturing of JP-1366 capsule 5 mg (zastaprazan citrate salt 5 mg)

[0079] A mixture was obtained by mixing 5 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, 220.8 mg of D-mannitol, 13.0 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.

[0080] The capsules manufactured in this way are referred to as ‘JP-1366 Capsule 5 mg’.

[0081] Manufacturing Example 3. Manufacturing of JP-1366 tablets 20 mg (zastaprazan citrate salt 20 mg)

[0082] 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.

[0083] The film-coated tablet manufactured in this way is referred to as ‘JP-1366, 20 mg.’

[0084] Manufacturing Example 4. Manufacturing of JP-1366 capsule 20 mg (zastaprazan citrate salt 20 mg)

[0085] 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.

[0086] The capsules manufactured in this way are referred to as ‘JP-1366 Capsule 20 mg’.

[0087] Manufacturing Example 5. JP-1366 capsule 20 mg placebo

[0088] A 20 mg placebo capsule of zastaprazan was manufactured in the same manner as in Manufacturing Example 4, except that the main ingredient, zastaprazan citrate salt, was not used. The capsule manufactured in this manner is referred to as 'JP-1366 capsule 20 mg placebo'.

[0089] Example 1. In vitro efficacy test against Helicobacter pylori (H. pylori)

[0090] An experiment was conducted to determine whether zastaprazan has growth inhibition or urease activity inhibition effects against Helicobacter pylori (H. pylori) under in vitro experimental conditions.

[0091] 1. Test substance

[0092] a. Drugs

[0093] The drugs used in the in vitro experiment are as shown in Table 1 below.

[0094] Drug name CAS No. Manufacturer Purity Zastaprazan (JP-1366) 2133852-18-1 Jeil Pharmaceutical 99.97% Omeprazole 73590-58-6 TCI>98.0% (HPLC) (T) Amoxicillin Trihydrate 61336-70-7 TCI>98.0% (T) Clarithromycin 81103-11-9 TCI>98.0% (T) Fexuprazan 1902954-60-2 Chemscene 99.58%

[0095] B. Reagents

[0096] The reagents used in the in vitro experiment are as shown in Table 2 below.

[0097] Drug NameCAS No.ManufacturerPurityBrain Heart Infusion237500BD (Difco)N / AMuller-Hinton broth275730BD (Difco)N / ABacto-agar214010BD (Difco)N / ALaked Horse BloodN / AOxoidN / AIsovitalexN / ABD (BBL)N / AHorse serumN / ASigma-Aldrichhemoglobin, ≤20 mg / dLCampyGenN / AOxoidN / A

[0098] B. Bacterial strain

[0099] Helicobacter pylori (ATCC43504): Type strain for antibiotic susceptibility testing according to CLSI guidelines.

[0100] Helicobacter pylori26695 (ATCC700329): A strain isolated from a British patient known to be associated with the development of gastric cancer. It is cytotoxin associated gene (CagA) and vacuolating cytotoxin (VacA) positive, and its genetic background is well known, making it a strain mainly used for research purposes.

[0101] Helicobacter pyloriSS1 (mouse colonizing strain): Known as the Sydney strain, it is CagA-positive and VacA-positive and was used in animal experiments as a strain that was confirmed to colonize C57BL / 6 mice.

[0102] A. Device

[0103] The equipment used in the in vitro experiment is as shown in Table 3 below.

[0104] Equipment Name Manufacturer Specification 37℃ incubatorVision BionicsVision / VS-1203P3VMicrocentrifugeGyrozen1730RSpectrophotometerBIO-RADBR170-2525Microplate readerMolecular DevicesSpectraMaxABS

[0105] 2. Badge preparation

[0106] a. Culture medium

[0107] Liquid media were prepared using Brain Heart Infusion (BHI; Difco, Sparks, MD, USA), 7% differentiation media (horse serum; Sigma Co. St. Louis, USA), and 0.4% Isovitalex (BBL; Sparks, MD, USA), and solid media were prepared using BHI supplemented with 7% laked horse blood (Oxoid Ltd, Basingstoke, Hants, UK), 0.4% Isovitalex, and 1.5-2% Bacto-agar (Difco, Sparks, MD, USA).

[0108] B. Medium for measuring minimum inhibitory concentration (MIC)

[0109] Prepared using Muller Hinton broth (MH, Difco, Sparks, MD, USA) [w / 7% differentiation medium (Sigma Co. St. Louis, USA), 0.4% isovitalex (BBL, Sparks, MD, USA)].

[0110] 3. In-vitro efficacy test - Minimum growth inhibition concentration (MIC) and minimum bactericidal concentration (MBC) of zastaprazan (JP-1366) against Helicobacter pylori

[0111] (1) Method

[0112] Antibiotic susceptibility testing was performed using the microdilution method according to the CLSI guidelines. Amocixillin and clarithromycin were serially diluted 2-fold to a maximum concentration of 128 μg / mL, and omeprazole was serially diluted 12-fold, starting with 256 μg / mL, in a 48-well plate. A positive control group was inoculated with bacteria into wells containing only medium without antibiotics, while a negative control group was inoculated with medium without antibiotics or bacteria. The concentration ranges for the test substances, zastaprazan (JP-1366) and fexuprazan, were determined through preliminary experiments. Helicobacter pylori (H. pylori) stored in a deep freezer (-70℃ or lower) was thawed and inoculated onto BHI agar (w / 7% Laked Horse blood, 0.4% isovitalex). Cultured for 3 days at 37℃ under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 gas, and then subcultured onto new medium. The cultured bacteria were harvested, suspended in PBS, and 5 x 10 5After inoculating each well at a concentration of 10 cfu / mL, culture for 3 days at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 gas. The lowest concentration at which no bacterial growth is observed is determined as the minimum growth inhibitory concentration (MIC). Afterwards, 10 μL of the culture from each concentration well is spotted onto BHI agar (w / 7% Laked Horse blood, 0.4% Isovitalex) without antibiotics, and cultured for 3 days at 37°C under microaerophilic conditions. The lowest concentration at which no bacterial growth occurs is determined as the minimum bactericidal concentration (MBC).

[0113] (2) Experimental results and interpretation

[0114] MIC determination is performed by visual inspection and measuring absorbance at 600 nm, and growth is confirmed based on the absorbance of the negative control group containing only medium. MBC determination is determined by spotting 10 μl of the culture solution from each well onto solid medium containing no antibiotics or test substances and confirming bacterial growth after MIC determination.

[0115] The suitability of the system for this test is controlled at the level of the result as the MIC value of amoxicillin for the type strain H. pylori ATCC43504.

[0116] All tests are conducted in duplicate, and the results are determined by conducting three repeated experiments.

[0117] Referring to Table 4 below, since the solubility of zastaprazan (JP-1366) is low, MIC analysis is difficult (poor solubility, formation of suspension, interference in visual / absorbance analysis), so the inhibitory effect on H. pylori strains was confirmed through the MBC index.

[0118] In the case of the test substance, Zastaprazan (JP-1366), it was confirmed that the inhibitory effect against three types of H. pylori strains was at least 2 times and up to 16 times better than that of Omeprazole and Fexuprazan in the case of MBC.

[0119] strainsJP1366AmoxicillinClarithromycinOmeprazoleFexuprazanMICMBCMICMBCMICMBCMICMBCMICMBC43504nd8~320.016~0.0320.0320.0320.0633 2646464~12826695nd16~320.016~0.0320.0320.063~0.1250.12532~6464~ 1286464~128SS1nd16~320.125~0.250.250.0320.12532~6464~1286464~128

[0120] Example 2. Anti-Helicobacter pylori (H. pylori) efficacy trial in patients with erosive gastroesophageal reflux disease (phase 2 clinical trial)

[0121] 1. Subject selection

[0122] Helicobacter pylori (H. pylori) test

[0123] Helicobacter pylori (H. pylori) testing was performed by 13C-urea breath test (13C-UBT), gastroscopy (CLO), or biopsy to determine H. pylori positivity / negativity. The tests were performed at the screening visit (Visit 1) or the randomization visit (Visit 2). Results obtained within 29 days prior to the randomization visit (Visit 2) at the same institution could be substituted.

[0124] Selection criteria

[0125] Subjects were required to meet all of the following inclusion criteria to participate in this clinical trial, unless otherwise specified.

[0126] 1) Adult men and women aged 19 to 75 as of the date of written consent

[0127] 2) Those who experienced heartburn or acid reflux symptoms within 7 days prior to the screening visit (Visit 1)

[0128] Heartburn, burning sensation inside the breastbone (sternum), pain inside the breastbone (sternum), burning sensation in the center of the upper abdomen (pituitary gland), pain in the center of the upper abdomen (pituitary gland), acid reflux, acid coming back up, symptoms of stomach contents (stomach acid or food) flowing back into the esophagus

[0129] 3) Those diagnosed with grade A or higher erosive gastroesophageal reflux disease according to the Los Angeles Classification through upper gastrointestinal endoscopy at the same institution within 29 days prior to the randomization visit (Visit 2)

[0130] LA grading criteria: A. When there is one or more mucosal defects in the esophagus that are less than 5 mm in length; B. When there is one or more mucosal defects in the esophagus that are 5 mm or more in length; C. When the mucosal defects in the esophagus are combined but do not exceed 75% of the esophageal circumference; D. When the mucosal defects in the esophagus are combined and exceed 75% of the esophageal circumference.

[0131] 4) A person who can complete the questionnaire and subject diary

[0132] 5) Those who have voluntarily agreed in writing to participate in this clinical trial

[0133] Exclusion criteria

[0134] If any of the following criteria were met, the patient was excluded from this clinical trial.

[0135] 1) Excluded diseases

[0136] (1) Those with Barrett's esophagus exceeding 3 cm or with significant dysplastic changes as determined by upper gastrointestinal endoscopy at the time of screening visit (Visit 1)

[0137] (2) Eosinophilic esophagitis (but may be included if esophageal biopsy is negative)

[0138] (3) Those with primary esophageal motility disorder or esophageal stricture

[0139] (4) Esophageal varices

[0140] (5) Those who have gastrointestinal bleeding or other abnormal bleeding on upper gastrointestinal endoscopy at the time of screening visit (Visit 1)

[0141] (6) Those who have undergone gastric acid suppression surgery or gastric or esophageal surgery. However, registration is possible if the following conditions apply:

[0142] ① Appendectomy, cholecystectomy, polypectomy

[0143] ② In case of endoscopic malignant tumor resection or endoscopic resection of early gastric cancer (EMR, ESD), if the patient has been cured and has not recurred for more than 5 years from the date of diagnosis

[0144] (7) Those with active duodenal ulcer, gastric ulcer, or pancreatitis

[0145] (8) Zollinger-Ellison syndrome

[0146] (9) People with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD)

[0147] (10) Those with warning symptoms (e.g., dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stool) that may be suspected of being a malignant disease of the gastrointestinal tract at the investigator's discretion (however, registration is possible only if the tumor is confirmed through an upper gastrointestinal endoscopy and the result is negative)

[0148] 2) Past medical history and concomitant diseases

[0149] (1) Those with clinically significant liver, kidney, nervous system, respiratory system, endocrine system, hematological tumor, cardiovascular system, or urinary system diseases

[0150] (2) Those with a history of malignant tumor within 5 years prior to the screening visit (Visit 1) (However, those who have been cured and have passed 5 years or more from the date of diagnosis without recurrence may register, but those with a history of malignant tumor of the digestive system or tumor resection (e.g., gastric resection, colectomy, etc.) excluding cases falling under (1)-(6) are not eligible for registration.)

[0151] (3) Those who have had experience with alcohol or drug abuse within 1 year prior to the screening visit (Visit 1)

[0152] (4) Persons with a confirmed history of human immunodeficiency virus (HIV)

[0153] (5) Those diagnosed with a mental illness that may affect the progress of this clinical trial (e.g., schizophrenia, dementia)

[0154] 3) Laboratory test results (at the time of screening visit)

[0155] (1) Those whose serum AST, ALT, ALP, γ-GT, or total bilirubin levels are more than twice the upper limit of normal.

[0156] (2) Those whose serum BUN or serum creatinine levels are more than twice the upper limit of normal

[0157] (3) Active hepatitis B or C (registration possible if no virus is detected)

[0158] 4) Medication / treatment history

[0159] (1) A person who is taking a drug that is prohibited from being used in combination or is expected to take it during the clinical trial period.

[0160] 5) History of hypersensitivity

[0161] (1) Patients with a history of hypersensitivity to the clinical trial drug, Nexium tablets (Esomeprazole), or benzimidazoles, penicillin antibiotics, or macrolide antibiotics.

[0162] 6) Others

[0163] (1) Pregnant women, breastfeeding women, women who have tested positive in a pregnancy test, or women or men of childbearing potential who plan to become pregnant during the clinical trial period

[0164] (2) In the case of female subjects and female partners of male subjects who are of childbearing age and have not undergone sterilization surgery, those who do not agree to use the following contraceptive methods during the clinical trial period.

[0165] (3) Those who received other clinical trial drugs within 1 month prior to the screening visit (Visit 1)

[0166] (4) Other than the above, those who the investigator determines are not suitable for participation in this clinical trial.

[0167] 2. Clinical trial method

[0168] This randomized, double-blind, active-controlled, multicenter, phase 2 clinical trial will be conducted on patients with erosive gastroesophageal reflux disease (GERD). Subjects will undergo a screening examination after giving written consent to participate in the trial. If they are taking medications that may affect the gastric mucosa at the time of screening, they will undergo an upper gastrointestinal endoscopy after a two-week drug-free period (except for potassium-competitive acid blockers (P-CABs) or proton pump inhibitors (PPIs), a four-week drug-free period). Subjects who meet the inclusion / exclusion criteria based on the screening results will be randomly assigned to study group 1, study group 2, or the control group in a 1:1:1 ratio. At this time, the assignment will be stratified by grade (A, B, C, D) according to the LA classification system determined by upper gastrointestinal endoscopy. Randomly assigned subjects will take the investigational drug once daily for four weeks according to their assigned treatment group. Subjects will visit the study institution after four weeks of administration of the investigational drug to undergo an upper gastrointestinal endoscopy to assess whether they have recovered. Cured subjects will undergo a Safety Follow-Up (F / U) two weeks later. Uncured subjects will receive the investigational drug for an additional four weeks (a total of eight weeks of administration) and then return to the study institution for an upper gastrointestinal endoscopy. Regardless of whether they have recovered, a Safety Follow-Up (F / U) will be performed two weeks later.

[0169] 3. Dosage, administration period, and administration method

[0170] a. Dosage

[0171] - Test drug 1: JP-1366, 5 mg 2 capsules (zastaprazan citrate salt 10 mg)

[0172] - Test drug 2: JP-1366, 20 mg 1 capsule (zastaprazan citrate salt 20 mg)

[0173] - Control drug: Esomeprazole magnesium trihydrate 44.5 mg (40 mg as Esomeprazole, 1 Nexium tablet 40 mg)

[0174] B. Administration period

[0175] Test period per subject: Up to 14 weeks

[0176] - Screening period: 15 or 29 days

[0177] - Dosage period: 4 weeks (or 8 weeks)

[0178] - Safety F / U period: 2 weeks after the last administration of the clinical trial drug

[0179] D. Dosage method

[0180] Depending on the randomly assigned administration group, administer the clinical trial drug orally once a day on an empty stomach at regular intervals, if possible, for 4 weeks (or 8 weeks*) starting from the day of administration.

[0181] *Only for subjects whose mucosal defects have not healed after 4 weeks of administration of clinical trial drugs, an additional 4-week administration period will be administered.

[0182] 4. Validity evaluation variables

[0183] A. Primary efficacy endpoint:

[0184] Cumulative healing rate of mucosal defects up to 8 weeks after administration of clinical trial drug (%)

[0185] * Upper gastrointestinal endoscopy revealed that the lesion had returned to normal mucosa.

[0186] B. Secondary efficacy endpoints:

[0187] ① Mucosal defect healing rate (%) up to 4 weeks after administration of clinical trial drug

[0188] ② Symptom assessment through subject diary

[0189] A. Evaluation of symptoms (heartburn, acid reflux, heartburn and acid reflux) within 24 hours after administration of the clinical trial drug

[0190] B. Evaluation of symptoms (heartburn, acid reflux, heartburn and acid reflux) for 7 days after administration of the clinical trial drug

[0191] C. The day of reaching CR (disappearance of heartburn and acid reflux for 7 days) after administration of the clinical trial drug

[0192] D. Proportion of symptom-free days (heartburn, acid reflux, heartburn and acid reflux) at 4 and 8 weeks after administration of the investigational drug (daytime, nighttime, daytime and nighttime)

[0193] ③ Gastroesophageal Reflux Disease Symptom Assessment (RDQ) Changes in frequency and severity of each major symptom at 4 and 8 weeks of clinical trial drug administration compared to baseline

[0194] ④ Change in total score at 4 and 8 weeks of administration of clinical trial drug compared to baseline in quality of life assessment (GERD-HRQL)

[0195] 5. Safety evaluation variables

[0196] (1) Adverse reactions

[0197] (2) Vital signs

[0198] (3) Laboratory tests

[0199] (4) Electrocardiogram (12-layer ECG)

[0200] (5) Physical examination

[0201] 6. Statistical analysis method

[0202] A. Primary efficacy evaluation variable

[0203] Cumulative healing rate of mucosal defects up to 8 weeks after administration of clinical trial drug (%)

[0204] The proportion of subjects whose erosions recovered to normal mucosa from the first administration of the clinical trial drug to the 8-week point and the two-sided 95% confidence intervals are presented by administration group. To compare each treatment 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, adjusted for baseline LA grade (A, B, C, D) as a stratification factor, was used to obtain the lower limit of each two-sided 95% confidence interval.

[0205] B. Secondary efficacy evaluation variables

[0206] ① Mucosal defect healing rate (%) up to 4 weeks after administration of clinical trial drug

[0207] The proportion of subjects whose erosions recovered to normal mucosa at 4 weeks after the first administration of the clinical trial drug and the two-sided 95% confidence intervals are presented by administration group. To compare each treatment group with the control group (JP-1366 10 mg vs. Nexium tablets 40 mg, JP1366 20 mg vs. Nexium tablets 40 mg), the Cochran-Mantel-Haenszel method, adjusted for baseline LA grade (A, B, C, D) as a stratification factor, was used to obtain the lower limit of each two-sided 95% confidence interval.

[0208] ② Symptom assessment through subject diary

[0209] A. Evaluation of symptoms (heartburn, acid reflux, heartburn, and acid reflux) within 24 hours after administration of the investigational drug: Comparison of the mean of the evaluation of symptoms (heartburn, acid reflux, heartburn, and acid reflux) within 24 hours after administration of the first investigational drug between each test group and the control group is analyzed using an ANCOVA (Analysis of covariance) model with baseline LA grade (A, B, C, D) as a covariate.

[0210] B. Evaluation of symptoms (heartburn, acid reflux, heartburn, and acid reflux) for 7 days after administration of the investigational drug: Comparison of the mean of the evaluation of symptoms (heartburn, acid reflux, heartburn, and acid reflux) for 7 days after the first administration of the investigational drug between each test group and the control group is analyzed using an ANCOVA model with baseline LA grade (A, B, C, D) as a covariate.

[0211] C. The day of reaching CR (disappearance of heartburn and acid reflux for 7 days) after administration of the investigational drug: If the symptom score is 0 for 7 consecutive days after the first administration of the investigational drug, it is defined as CR (disappearance of heartburn and acid reflux for 7 days), and the event is based on the first CR. If there is no CR, it is treated as censored. Kaplan-Meier plots and medians and two-sided 95% confidence intervals are presented for each administration group, and the comparison of each test group to the control group is analyzed using the stratified log-rank test adjusted for the baseline LA grade as a stratification factor.

[0212] D. Proportion of symptom-free days (heartburn, acid reflux, heartburn and acid reflux) during 4 and 8 weeks after administration of the investigational drug (daytime, nighttime, daytime and nighttime): Comparison of each test group with the control group in the proportion of symptom-free days (heartburn, acid reflux, heartburn and acid reflux) during 4 and 8 weeks after administration of the first investigational drug during the daytime, nighttime, daytime and nighttime, respectively, is analyzed using an ANCOVA model with baseline LA grade (A, B, C, D) as a covariate.

[0213] ③ Gastroesophageal Reflux Disease Symptom Assessment (RDQ) Baseline vs. 4-week and 8-week administration changes in frequency and severity of each symptom between the control group and the test group are analyzed using an ANCOVA model with baseline LA grade (A, B, C, D) as a covariate. The same statistical analysis as above is performed on the change in the last result excluding the baseline compared to the baseline.

[0214] ④ Quality of Life Assessment (GERD-HRQL) The change in the total quality of life score after 4 and 8 weeks of administration compared to the baseline was analyzed using an ANCOVA model with the baseline LA grade (A, B, C, D) as a covariate. The same statistical analysis as above was performed on the change in the last outcome excluding the baseline compared to the baseline.

[0215] D. Safety evaluation variables

[0216] For subjects who experienced at least one adverse reaction (or adverse drug reaction), the number of occurrences and incidence rates and their two-sided 95% confidence intervals are presented for each treatment group. To test whether there is a difference in the incidence rates of adverse reactions (or adverse drug reactions) between the control group and each test group, the Chi-square test or Fisher's exact test is performed. In addition, the latest version of MedDRA (Medical Dictionary for Regulatory Activities) is used to code and present the data by SOC (System Organ Class) and PT (Preferred Term). Serious adverse reactions, adverse reactions leading to discontinuation of clinical trial drug administration, and adverse reactions leading to death are also summarized by SOC (System Organ Class) and PT (Preferred Term) using the latest version of MedDRA. For laboratory tests, vital signs, and electrocardiograms (12-lead ECGs), descriptive statistics (number of subjects, mean, standard deviation, median, minimum, maximum) for continuous data by visit and change from baseline are presented, and contingency tables are created for categorical data. For laboratory tests and electrocardiograms (12-lead ECGs), to determine changes from baseline after administration of the investigational drug, normal or clinically insignificant abnormalities (Normal or Abnormal NCS) and clinically significant abnormalities (Abnormal CS) are summarized at each assessment time point in the form of a shift table. For physical examinations, a list of subjects who were normal or clinically insignificant abnormalities (Abnormal NCS) at baseline but changed to clinically significant abnormalities (Abnormal CS) after administration of the investigational drug is presented.

[0217] 7. Phase 2 clinical trial results

[0218] A. Check whether symptoms have improved

[0219] In the evaluation of all symptoms (heartburn, acid reflux, heartburn / acid reflux) within 24 hours and for 7 days after administration of the clinical trial drug, it was confirmed that all symptoms tended to improve within 24 hours and for 7 days after administration of the clinical trial drug 1 and 2.

[0220] B. Check the healing rate

[0221] (1) Helicobacter pylori (H. pylori) positive group (infection group)

[0222] In the JP-1366 20 mg (Zastaprazan 20 mg) administration group, 100% healing effect was observed at both 4 and 8 weeks, but Nexium 40 mg showed 87.5% effect (see Table 7).

[0223] JP-1366 10 mg (N=7) JP-1366 20 mg (N=5) Esomeprazole 40 mg (N=8) Healing rate at 4 weeks, n (%) 6 (85.71) 5 (100.00) 7 (87.50) Healing rate at 8 weeks, n (%) 7 (100.00) 5 (100.00) 7 (87.50)

[0224] (2) Helicobacter pylori (H. pylori) negative group

[0225] The JP-1366 20 mg (Zastaprazan 20 mg) group demonstrated the same efficacy as Nexium 40 mg (see Table 8). This clinical trial demonstrated that Zastaprazan can achieve the same efficacy as the control group, Nexium 40 mg, even at a significantly lower dose.

[0226] JP-1366 10 mg (N=41) JP-1366 20 mg (N=42) Esomeprazole 40 mg (N=41) Healing rate at 4 weeks, n (%) 39 (95.12) 38 (90.48) 37 (90.24) Healing rate at 8 weeks, n (%) 40 (97.56) 41 (97.62) 40 (97.56)

[0227] (3) Overall healing rate

[0228] Considering the results of the H. pylori positive group (infection group) and the H. pylori negative group, the overall cure rate was 93.75% (45 / 48 subjects) in the JP-1366 10 mg group, 91.49% (43 / 47 subjects) in the JP-1366 20 mg group, and 89.80% (44 / 49 subjects) in the esomeprazole 40 mg group.

[0229] (4) Conclusion

[0230] Nexium 40 mg showed a higher cure rate for erosions in patients negative for Helicobacter pylori (H. pylori) than in patients positive for Helicobacter pylori (H. pylori), but the pharmaceutical composition according to the present invention showed a therapeutic effect on gastroesophageal reflux disease and / or peptic ulcer regardless of the presence or absence of Helicobacter pylori (H. pylori) infection, and rather, it was confirmed that it tended to show a high effect in patients infected with Helicobacter pylori (H. pylori). It can be seen that this is due to the bactericidal effect of zastaprazan itself in the pharmaceutical composition according to the present invention.

[0231] Example 3. Anti-Helicobacter pylori (H. pylori) efficacy trial in patients with erosive gastroesophageal reflux disease (phase 3 clinical trial)

[0232] 1. Subject selection

[0233] Helicobacter pylori (H. pylori) test

[0234] Helicobacter pylori (H. pylori) testing was performed by 13C-urea breath test (13C-UBT), upper gastrointestinal endoscopy (CLO), or biopsy to determine H. pylori positivity / negativity. The tests were performed at the screening visit (Visit 1) or the randomization visit (Visit 2). Results obtained within 29 days prior to the randomization visit (Visit 2) at the same institution could be substituted.

[0235] Selection criteria

[0236] Subjects were required to meet all of the following inclusion criteria to participate in this clinical trial, unless otherwise specified.

[0237] 1. Men and women aged 19 or older as of the date of written consent

[0238] 2. Those who experienced heartburn and acid reflux within 7 days prior to the screening visit, and whose severity and frequency of symptoms correspond to 1) or 2) below.

[0239] 1) Those who have experienced mild or more severe heartburn or acid reflux at least twice a week

[0240] 2) Those who have experienced moderate or severe heartburn or acid reflux at least once a week

[0241] 3. Those diagnosed with grade A or higher erosive esophagitis according to the Los Angeles Classification† based on an endoscopic examination performed within 15 days of randomization.

[0242] † LA classification

[0243] GradeEndoscopic findingAOne (or more) mucosal break no longer than 5 mm, that does not extend between the tops of two mucosal foldsBOne (or more) mucosal break more than 5 mm long, that does not extend between the tops of two mucosal foldsCOne (or more) mucosal break that is continuous between the tops of two or more mucosal folds, but which involves less than 75% of the circumferenceDOne (or more) mucosal break which involves at least 75% of the esophageal circumference

[0244] 4. Those who have fully understood this clinical trial and voluntarily agreed in writing to participate in the clinical trial.

[0245] Exclusion criteria

[0246] If any of the following criteria were met, the patient was excluded from this clinical trial.

[0247] The subject must not meet any of the following criteria:

[0248] 1. Those who cannot undergo endoscopy

[0249] 2. Troops

[0250] 1) Those with warning symptoms (dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stool, etc.) that may suggest a malignant disease of the gastrointestinal tract (excluding those who have tested negative for malignancy through an endoscopic examination)

[0251] 2) Patients with eosinophilic esophagitis (excluding those whose esophageal biopsy results are negative)

[0252] 3) Those with gastroesophageal stenosis, gastroesophageal varices, Barrett's esophagus, active peptic ulcer, gastrointestinal bleeding, or gastrointestinal malignancy confirmed by endoscopy.

[0253] 4) Patients with Zollinger-Ellison syndrome

[0254] 5) Those with a history or suspected history of primary esophageal motility disorder, irritable bowel syndrome (IBS), or inflammatory bowel disease (IBD), including pancreatitis, within the past 3 months.

[0255] 6) Those who have undergone gastric acid suppression surgery, gastrointestinal surgery, or esophageal surgery (excluding appendectomy, cholecystectomy, and polypectomy)

[0256] 7) Those with clinically significant liver, kidney, cardiovascular, respiratory, endocrine, urinary, neuropsychiatric, or hematological diseases.

[0257] 8) Those with a history of malignant tumor within the past 5 years prior to screening. However, those with a history of gastrointestinal malignancy are excluded regardless of the period of screening.

[0258] 3. Those who show the following abnormal test results in laboratory tests conducted at the time of screening for laboratory tests.

[0259] 1) ALT or AST > 2.0 x ULN

[0260] 2) Total bilirubin > 2.0 x ULN

[0261] 3) ALP or GGT > 2.0 x ULN

[0262] 4) eGFR R<70 mL / min / 1.73 m 2 (CKD-EPI formula)

[0263] 5) Positive results of serum tests (HBsAg, HCV Ab, HIV Ab, Syphilis reagin test)

[0264] 6) Those who show clinically significant abnormal findings in electrocardiogram examination

[0265] 4. Allergies and drug hypersensitivity reactions

[0266] 1) Persons known to have hypersensitivity to the components or additives of clinical trial drugs

[0267] 2) Those with a history of clinically significant allergic disease (excluding mild allergic rhinitis that does not require medication) or hypersensitivity to other drugs (aspirin, antibiotics, etc.)

[0268] 5. Contraindicated drugs and treatments

[0269] 1) Those who took acid secretion inhibitors such as potassium-competitive acid blockers (P-CABs) or proton pump inhibitors (PPIs) within 2 weeks prior to the endoscopy at the time of screening.

[0270] 2) Those who took reflux esophagitis-related medications (antacids, gastrointestinal motility promoters, histamine-2 receptor antagonists) more than twice within 1 week prior to the endoscopy at the time of screening.

[0271] 3) Those who cannot stop taking drugs that may cause ulcers, such as aspirin or non-steroidal anti-inflammatory drugs (NSAIDs), during the clinical trial period.

[0272] 4) Those who are taking or need to take medications that are contraindicated for concomitant use in this clinical trial. However, those taking contraindicated medications may participate after a two-week washout period. If the period corresponding to five times the half-life of the contraindicated medication exceeds two weeks, the washout period will be five times the half-life of the drug.

[0273] 6. Pregnant and lactating women

[0274] 7. Subjects and spouses (or partners) who did not use medically acceptable contraception during the entire period of the contraceptive clinical trial.

[0275] 1) Use of an intrauterine device with a proven pregnancy failure rate

[0276] 2) Use of double-barrier contraception (male condom and closure cap, diaphragm or cervical cap) and simultaneous use of spermicide

[0277] 3) Infertility treatments (vasectomy, salpingectomy and ligation, hysterectomy)

[0278] 8. Those with a history of clinically significant mental illness, drug or alcohol abuse

[0279] 9. Those who are judged by other investigators to be inappropriate for participation in this clinical trial.

[0280] 2. Clinical trial method

[0281] Those who voluntarily consent to participate in this clinical trial will undergo a screening visit, and only eligible subjects will be selected based on the inclusion / exclusion criteria. Eligible subjects will be randomly assigned to the experimental or control group and will receive the investigational drug according to their assigned group at the baseline visit (V2). Visits will be held on Days 1 and 4 of the four-week treatment period, and the investigational drug will be administered orally once daily.

[0282] 3. Dosage, administration period, and administration method

[0283] a. Dosage

[0284] - Test drug: JP-1366, 20 mg 1 capsule (Zastaprazan citrate salt 20 mg)

[0285] - Control drug: Esomeprazole magnesium trihydrate 44.5 mg (40 mg as Esomeprazole, 1 Nexium tablet 40 mg)

[0286] B. Administration period

[0287] About 12 weeks (±14 days)

[0288] 1. Screening period: Up to 2 weeks from the first administration of the clinical trial drug

[0289] 2. Treatment period: 4 weeks (± 7 days) after the first administration of the clinical trial drug

[0290] 3. Follow-up visit: 2 weeks (±14 days) after the last administration of the clinical trial drug

[0291] D. Dosage method

[0292] - Administer orally once a day for a total of 4 weeks at regular intervals, regardless of meals, according to the randomly assigned administration group.

[0293] Administration group Clinical trial drug Test group JP-1366 20 mg 1 capsule, Esomeprazole placebo 1 tablet ●◇Control group JP-1366 placebo 1 capsule, Esomeprazole 40 mg 1 tablet ○◆●: JP-1366 20 mg◆: Esomeprazole 40 mg○: JP-1366 placebo◇: Esomeprazole placebo

[0294] 4. Concomitant medications

[0295] A. Concurrent medications

[0296] The following drugs are contraindicated during this clinical trial.

[0297] 1. All gastric acid secretion inhibitors other than clinical trial drugs

[0298] 2. Gastric mucosal protective agent

[0299] 3. Antacids

[0300] 4. Gastrointestinal motility stimulant

[0301] 5. Other gastrointestinal medications

[0302] 6. Steroid preparations (local administration, epidural administration, and inhalation administration are permitted)

[0303] 7. Non-steroidal anti-inflammatory drugs (however, short-term use of NSAIDs for the treatment of acute pain is permitted at the investigator's discretion)

[0304] 8. Cholinergics, antipsychotics, antithrombotics (anticoagulants or antiplatelet agents (including aspirin))

[0305] 9. Drugs known to interact with clinical trial drugs

[0306] B. Concomitant medications

[0307] 1. Medications administered to treat concomitant diseases may be used without changes in dosage or route of administration. However, if the medication is determined not to affect the clinical trial, changes in dosage or route of administration may be permitted. Other medications may be administered concomitantly if they are determined not to affect the clinical trial.

[0308] 2. The use of drugs for pretreatment of endoscopic examination and urea breath test (UBT) is permitted.

[0309] 5. Phase 3 clinical trial results

[0310] A. Confirm the healing rate of mucosal breaks

[0311] (1) Confirmation of the cumulative healing rate of mucosal defects in test subjects who tested positive (infected) with Helicobacter pylori (H. pylori)

[0312] The cumulative healing rate of mucosal defects according to Helicobacter pylori (H. pylori) infection refers to the proportion of subjects whose mucosal defects were healed as determined by endoscopic examination within 4 weeks after administration of the clinical trial drug.

[0313] The frequency and percentage of mucosal defects healed at 4 weeks after administration of the investigational drug were presented by administration group according to the presence or absence of Helicobacter pylori (H. pylori) infection. Differences between administration groups (experimental group - control group) were analyzed using the Cochran-Mantel-Haenszel method, which adjusted the baseline LA classification as a stratification factor, and 95% confidence intervals for the differences were presented.

[0314] PPS (Per Protocol Set)

[0315] As a result of the PPS analysis, which is the main analysis group of this clinical trial, the number of subjects who tested positive for Helicobacter pylori (H. pylori) was 26 in the test group and 22 in the control group. The proportion of subjects whose mucosal defects were healed on endoscopy at 4 weeks 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).

[0316] FAS (Full Analysis Set)

[0317] According to the FAS analysis results, 28 subjects in the test group and 25 subjects in the control group tested positive for Helicobacter pylori (H. pylori). The percentage of subjects whose mucosal defects were healed on endoscopic examination at 4 weeks after administration of the clinical trial drug was 96.43% (27 / 28 subjects) in the test group and 80.00% (20 / 25 subjects) in the control group. The test group showed an excellent effect with a significant difference compared to the control group at 4 weeks.

[0318] JP-1366 20 mg Esomeprazole 40 mg Number of subjects 2622 Healed subjects, n (%) 26 (100.00) 18 (81.82)

[0319] JP-1366 20 mg Esomeprazole 40 mg Number of subjects 2825 Healed subjects, n (%) 27 (96.43) 20 (80.00)

[0320] 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 composition for eradicating Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

2. A composition for eradicating Helicobacter pylori, wherein the pharmaceutically acceptable salt of zastaprazan in paragraph 1 is zastaprazan citrate salt.

3. A composition for eradicating Helicobacter pylori according to claim 1, wherein the composition for eradicating Helicobacter pylori comprises 10 mg, 20 mg or 40 mg of a pharmaceutically acceptable salt of zastaprazan.

4. A composition for eradicating Helicobacter pylori, wherein the composition for eradicating Helicobacter pylori in the first paragraph is administered once to three times a day.

5. A composition for eradicating Helicobacter pylori, wherein the composition for eradicating Helicobacter pylori in the first paragraph is administered once a day.

6. A composition for sterilizing Helicobacter pylori in the first paragraph, wherein the sterilizing composition is formulated as a solid oral preparation.

7. A composition for eradicating Helicobacter pylori in the 6th paragraph, wherein the solid oral preparation is 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.

8. A pharmaceutical composition for treating Helicobacter pylori comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

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

10. Use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for eradicating Helicobacter pylori.

11. Use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, for the manufacture of a medicament for eradicating Helicobacter pylori.