TW202535382A - Composition for helicobacter pylori eradication including zastaprazan or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention discloses to a composition for Helicobacter pylori eradication, including zastaprazan or a pharmaceutically acceptable salt thereof.

Description

Components for the eradication of Helicobacter pylori containing ZASTAPRAZAN or its medically acceptable salts.

This invention relates to a composition for the eradication of Helicobacter pylori (H. pylori), comprising Zastaprazan or a medically acceptable salt thereof, and more specifically, to a composition for the eradication of H. pylori comprising Zastaprazan, a medically acceptable salt thereof, its hydrate or solvent, or a mixture thereof, wherein the composition exhibits therapeutic efficacy against gastroesophageal reflux disease and/or peptic ulcers due to its own eradication action, regardless of the level of H. pylori infection, and is more likely to show high efficacy in patients infected with H. pylori.

Helicobacter pylori is a Gram-negative spiral bacterium that lives in the gastric mucosa of humans. It is classified as a Group 1 carcinogen by the World Health Organization (WHO), and approximately half of the adult population in South Korea is infected with it. Helicobacter pylori is a bacterium that parasitizes the gastric mucosa and continues to grow; it will not disappear on its own unless properly treated.

The exact route of Helicobacter pylori infection is not fully understood, but it is known to spread from person to person. It is understood that infection is closely related to the unique lifestyle of Koreans, thus exposing them to the risk of Helicobacter pylori infection.

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. It is also known to be associated with functional dyspepsia, unexplained iron deficiency anemia, and chronic idiopathic thrombocytopenic purpura or similar conditions.

A multicenter study of asymptomatic adults in South Korea showed that the serological prevalence in 2015 was 51.0%, showing a steady downward trend compared to previous years. This may be attributed not only to proactive treatment but also to improvements in economic conditions and sanitation.

First-line eradication of Helicobacter pylori involves taking a gastric acid secretion inhibitor and two antibiotics (amoxicillin and clarithromycin) for 14 consecutive days. The success rate is 70%–80%, but treatment failure often occurs when some patients stop taking the medication on their own. In these patients, treatment may be difficult due to drug-resistant strains.

Among the pathogenic factors of Helicobacter pylori, urease neutralizes gastric acid, allowing the bacteria to colonize 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 help collect various inflammatory cells.

Therefore, it is necessary to develop a novel treatment that can directly exert antibacterial or urease-inhibiting effects against Helicobacter pylori.

[Related Technical Documents][Patent Documents] (Patent Document 1) Korean Patent Publication No. 10-2000-0005291

The inventors have identified a need to research and develop novel therapeutic agents capable of exerting direct antibacterial action or urease inhibition against Helicobacter pylori (H. pylori). Therefore, the object of this invention is to provide a composition for bacterial eradication comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof, wherein the composition exhibits therapeutic efficacy against gastroesophageal reflux disease and/or peptic ulcers regardless of H. pylori infection status, and is particularly effective in patients infected with H. pylori.

In order to achieve the above objectives, the present invention discloses the following means.

In one aspect, the present invention provides a composition for the eradication of Helicobacter pylori, comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof.

Beneficial Effects The present invention’s composition for bacterial eradication comprises Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof, and the composition has the following advantages: regardless of Helicobacter pylori infection, the composition exhibits therapeutic effects on gastroesophageal reflux disease and/or peptic ulcers due to its own Helicobacter pylori eradication action, and is particularly effective in patients infected with Helicobacter pylori.

Furthermore, the composition of this invention for bacterial eradication has the following advantages: in the evaluation of all symptoms (heartburn, acid reflux, heartburn/acid reflux) caused by Helicobacter pylori infection, all symptoms tend to improve within 24 hours and for a period of 7 days.

The effects of this invention are not limited to those described above, but may include various effects that are obvious to those skilled in the art from the description below.

The invention will now be described in more detail.

The specific explanation is as follows. The terms used herein were selected from the most widely used general terms possible while considering the function of the invention. However, they may vary depending on the intent of those with ordinary knowledge in the field, precedents, the emergence of new technologies, etc. Furthermore, in some cases, there are terms arbitrarily chosen by the applicant, and in such cases, their meanings will be explained in detail in the corresponding sections of the detailed description of the invention. Therefore, the terms used herein should be defined based on their meanings and the overall content of the invention, rather than simply on their names.

Unless otherwise defined, all terms used herein, including technical and scientific terms, shall 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 common dictionaries, shall be interpreted as having a meaning consistent with their meaning in the relevant field context and shall not be interpreted in an idealized or overly formalized sense, unless so expressly defined in this invention.

The range of values includes the values defined therein. Each maximum value limit given throughout this specification includes each lower value limit as if such lower value limits were explicitly stated. Each minimum value limit given throughout this specification includes each higher value limit as if such lower value limits were explicitly stated. Each value limit given throughout this specification will include each better value range within a wider range of values as if the narrower value limit were explicitly stated.

Each description and embodiment disclosed herein can also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed herein fall within the scope of this invention. Furthermore, the scope of this invention should not be considered as limited by the specific descriptions below.

As used herein, expressions such as “include” should be understood as open-ended terms that imply the possibility of including other implementations, unless otherwise expressly stated in the phrase or sentence containing the expression.

As used herein, the term "Zastaprazan" may refer to Zastaprazan, its pharmaceutically acceptable salts, its hydrates or solvents, or mixtures thereof. Therefore, as used herein, "compositions containing Zastaprazan" may refer to compositions containing Zastaprazan, its pharmaceutically acceptable salts, its hydrates or solvents, or mixtures thereof.

The invention will now be described in detail.

A component containing Zastaprazan for the eradication of Helicobacter pylori.

This invention discloses a composition for the eradication of Helicobacter pylori (H. pylori) containing Zastaprazan.

Specifically, the present invention provides a composition for the eradication of Helicobacter pylori comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof.

The present invention comprises a bacterial eradication component comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof, and the component has the advantage that, regardless of Helicobacter pylori infection status, the component exhibits therapeutic efficacy against gastroesophageal reflux disease and/or peptic ulcers due to its own Helicobacter pylori eradication action, and is particularly effective in patients infected with Helicobacter pylori.

Furthermore, due to the unique reversible proton pump inhibition of Zastaprazan, the bacterial eradication formulation of this invention exhibits a synergistic effect in both Helicobacter pylori eradication and gastric acid secretion inhibition (potassium-competitive acid blocker; P-CAB), thereby demonstrating higher therapeutic efficacy in patients with Helicobacter pylori infection suffering from gastroesophageal reflux disease or peptic ulcers.

Furthermore, the composition of this invention for bacterial eradication has the following advantages: in the evaluation of all symptoms (heartburn, acid reflux, heartburn/acid reflux) caused by Helicobacter pylori infection, all symptoms tend to improve within 24 hours and for a period of 7 days.

In this 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.

In this invention, Zastaprazan is the active ingredient for the eradication of Helicobacter pylori.

The term "active ingredient" as used in this article refers to a substance or combination of substances that is expected to directly or indirectly exhibit the therapeutic effects and efficacy of a pharmaceutical composition through its inherent pharmacological action, and which includes a main component.

The Zastaprazan of this invention can exist in a pharmaceutically acceptable salt form, and as a salt, it is useful as an acid addition salt formed from a pharmaceutically acceptable free acid. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic acid addition salt of Zastaprazan whose concentration has a relatively non-toxic and harmless effect on the patient, and whose side effects do not diminish the beneficial therapeutic effects of Zastaprazan. 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, while 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, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid can be used.

Unless otherwise stated, the pharmaceutically acceptable salts of this invention include salts with acidic or basic groups that may be present in Zastaprazan. For example, pharmaceutically acceptable salts may include sodium salts, calcium salts, and potassium salts with hydroxyl groups, and pharmaceutically acceptable salts with other amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, mesylate, and tosylate, etc., and can be prepared by methods known in the art for preparing salts.

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

As used in this article, the term "hydrate" refers to a hydrate formed by the non-covalent intermolecular forces binding the active ingredient Zastaprazan or its pharmaceutically acceptable salt with water, and which contains stoichiometric or non-stoichiometric amounts of water. Specifically, based on 1 mol of the active ingredient, the hydrate may contain approximately 0.25 mol to approximately 10 mol of water, and more specifically, it may contain approximately 0.5 mol, approximately 1 mol, approximately 1.5 mol, approximately 2 mol, approximately 3 mol, approximately 5 mol, etc.

As used herein, "solvent" refers to a compound formed by the non-covalent intermolecular forces binding the active ingredient Zastaprazan or its pharmaceutically acceptable salt with a solvent, and which contains stoichiometric or non-stoichiometric amounts of solvent. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small quantities. Examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-acetic acid ester, 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 solvent of the present invention is not limited to these examples. Specifically, based on 1 mol of active ingredient, the solvent may contain a solvent in proportions of about 0.25 mol to about 10 mol, 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.

The term "bacterial eradication" used in this article has a similar meaning to sterilization and refers to the elimination of bacteria. This term refers to the state where metabolism stops without directly killing the microorganisms, until the microorganisms die after a certain period of time; that is, the state where bacterial proliferation and growth cease. In this article, Helicobacter pylori eradication can be considered to include eliminating or eradicating Helicobacter pylori present in the human stomach, or stopping the proliferation and growth of Helicobacter pylori.

In this invention, the composition can be administered once to three times daily. Specifically, Zastaprazan, its pharmaceutically acceptable salts, its hydrates or solvents, or mixtures thereof can be administered once to three times daily for one week or longer, or four weeks or longer, and for 24 weeks or less, or 12 weeks or less. Specifically, the composition can be administered once to three times daily for one to 24 weeks, two to 24 weeks, four to 24 weeks, one to 12 weeks, two to 12 weeks, or four to 12 weeks, and preferably for four to eight weeks, but is not limited thereto.

In this invention, Zastaprazan, its pharmaceutically acceptable salts, its hydrates or solvents, or mixtures thereof may contain amounts calculated as Zastaprazan (in free base form) of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg. Specifically, Zastaprazan, its pharmaceutically acceptable salts, its hydrates or solvents, or mixtures thereof may contain amounts calculated as Zastaprazan (in free base form) of about 3.3, 6.6, 13.1, 26.2, or 52.4 mg, and may contain amounts calculated as Zastaprazan citrate of 5 mg to 40 mg, specifically 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg. mg, and more specifically, in the form of Zastaprazan citrate, the amount is calculated as 10 mg or 20 mg. As stated above, the composition of the present invention, even when containing a low dose (10 mg or 20 mg) of Zastaprazan, exhibits a Helicobacter pylori eradication effect comparable to or greater than that of 40 mg Nexium tablets when administered once daily, thereby demonstrating 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 consecutive days after administration.

In this invention, the composition for bacterial eradication may include one or more pharmaceutical additives consisting of adductors, disintegrants, binders and lubricants, but is not limited thereto.

In this invention, the adjuvant may be one or more of microcrystalline cellulose, lactose monohydrate, anhydrous lactose, sucrose, dextrorotatory mannitol, starch, corn starch or light anhydrous silica, but is not limited thereto.

In this invention, the disintegrant may comprise starch or modified starch, such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch; clay, such as bentonite, montmorillonite, or veegum; cellulose, such as hydroxypropyl cellulose or carboxymethyl cellulose; alginate, such as sodium alginate or alginic acid; crosslinked cellulose, such as crosslinked carboxymethyl cellulose sodium; and gums, such as guar gum or xanthan gum. Cross-linked polymers, such as cross-linked povidone; foaming agents, such as sodium bicarbonate or citric acid, and their analogues. These can be used alone or in combination of two or more, but are not limited thereto.

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

In this invention, examples of lubricants may 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, and talc. These may be used alone or in combination of two or more, but are not limited thereto.

In this invention, the composition for bacterial eradication may be a solid oral formulation, but is not limited thereto.

In this invention, the solid oral preparation may be one of the following: tablets, film-coated tablets, capsules, powders, granules, pills, throat lozenges, oral jelly, and orally disintegrating film preparations, but is not limited thereto.

Specifically, for film-coated tablets, coating agents widely known in the art can be used, but are not limited to these.

Pharmaceutical components containing Zastaprazan for the treatment of Helicobacter pylori.

This invention provides a pharmaceutical composition for the treatment of Helicobacter pylori (H. pylori) comprising Zastaprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvent, or a mixture thereof.

Zastaprazan is the same as described above.

As used herein, the term "treatment" refers to the partial or complete relief, improvement, reduction, inhibition or delay of Helicobacter pylori infection, reduction of severity, or reduction of the occurrence of one or more symptoms or features by administering a composition according to the invention.

The above information regarding components for bacterial eradication can be applied to all therapeutic components, as long as they are not contradictory.

Methods for eradicating Helicobacter pylori, including administering pharmaceutical components to individuals in need.

This invention provides a method for eradicating Helicobacter pylori, the method comprising administering to an individual in need a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of Zastaprazan, a pharmaceutically acceptable salt thereof, its hydrate or solvent, or a mixture thereof.

The term "medically effective amount" as used in this article refers to an effective amount for eradicating Helicobacter pylori. For example, it refers to the amount of a component administered to an individual, which can include all components that can prevent the occurrence or recurrence of Helicobacter pylori, relieve symptoms, inhibit direct or indirect pathological consequences, prevent metastasis, slow the rate of progression, alleviate or temporarily relieve symptoms, or improve prognosis. In other words, a pharmaceutically effective amount can be interpreted as encompassing all dosages that can eradicate Helicobacter pylori through a component.

Specifically, in the method for eradicating Helicobacter pylori according to the present invention, Zastaprazan or its pharmaceutically acceptable salts, hydrates or solvents, or mixtures thereof may contain amounts calculated as zastaprazan (in free base form) of 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg. Specifically, zastaprazan or its pharmaceutically acceptable salts, hydrates or solvents, or mixtures thereof may contain amounts calculated as zastaprazan (in free base form) of approximately 3.3, 6.6, 13.1, 26.2, or 52.4 mg, or calculated as zastaprazan citrate of 5 to 40 mg. Specifically, calculated as zastaprazan citrate of 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg. mg, and more specifically, in the form of zastaprazan citrate, in amounts of 10 mg or 20 mg. Preferably, an individual may be given 5 to 40 mg of zastaprazan citrate once daily, and more preferably, an individual may be given 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg of zastaprazan citrate once daily to effectively treat the individual by eradicating Helicobacter pylori.

As used in this article, the term "individual" refers to mammals, and more specifically, mammals including humans include mammals such as humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice, and more specifically, it can mean humans. The individual can be a person infected or suspected of being infected with Helicobacter pylori due to causes such as gastroesophageal reflux, chronic gastritis, gastric or duodenal ulcers, and gastric cancer.

Here, the term "person infected with Helicobacter pylori" refers to someone confirmed to be infected with Helicobacter pylori through respiratory or stool examinations or upper gastrointestinal endoscopy due to symptoms such as gastroesophageal reflux symptoms (heartburn, acid reflux, and heartburn/acid reflux), upper abdominal pain, indigestion, or abdominal discomfort (bloating, abdominal distension, burning sensation). The term "person suspected of being infected with Helicobacter pylori" refers to the situation of having the above symptoms.

The above information regarding components used for bacterial eradication can be applied to all methods of bacterial eradication, as long as they are not contradictory.

Uses in eradicating Helicobacter pylori

This invention provides the use of a composition comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof, in the eradication of Helicobacter pylori.

The above-mentioned components for bacterial eradication can be applied to all uses in the eradication of Helicobacter pylori, as long as they are not contradictory.

Use in the preparation of drugs for the eradication of Helicobacter pylori

This invention provides the use of a composition comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof, in the preparation of a medicament for the eradication of Helicobacter pylori.

The composition of the present invention for preparing a drug can be mixed with an acceptable carrier or similar, and may further contain other agents.

The above-mentioned contents regarding components for bacterial eradication can be applied to all uses in the preparation of drugs for the eradication of Helicobacter pylori, provided that they are not contradictory.

The invention will be illustrated in more detail below using manufacturing examples and examples. It will be apparent to those skilled in the art that these manufacturing examples and examples are intended only to illustrate the invention more specifically, and are not intended to limit the scope of the invention.

The following preparation examples and the active ingredient used in the examples are zastaprazan citrate, which, for convenience, is named Zastaprazan or JP-1366.

Manufacturing Examples

Preparation Example 1. Preparation of Zastaprazan Citrate

Azacyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone citrate was obtained according to the following method. Specifically, azacyclobutane-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 NMR analysis results of the obtained azacyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone are described below.

1H 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).

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 resulting mixture was stirred and vacuum dried at about 30 to 35°C to obtain a dried product. About 10 g of the dried product was taken and stirred together with about 167 g of acetone. During this process, a solution prepared by dissolving citric acid (about 5 g) in acetone (about 33 g) was slowly added dropwise over 60 minutes, and the resulting mixture was stirred at the same temperature for one hour. The mixture was cooled to approximately 20°C to 25°C and stirred for one hour. The resulting solid was then filtered, washed with acetone, and dried under vacuum to obtain azidocyclobutane-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 azidocyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone citrate (Zastaprazan 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).

Preparation Example 2. Preparation of JP-1366 Capsules 5 mg (Zastaprazan Citrate 5 mg)

Five mg of aziridine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} methyl ketone citrate (Zastaprazan citrate) obtained according to Preparation Example 1 was mixed with 220.8 mg of dextrorotatory mannitol, 13.0 mg of sodium cross-linked carboxymethyl cellulose, and 1.2 mg of magnesium stearate to obtain a mixture. This mixture was then filled into a No. 1 hard capsule used as the capsule base to prepare a capsule formulation.

The capsule preparation made in this way is called "JP-1366 Capsules 5 mg".

Preparation Example 3. Preparation of JP-1366 tablets 20 mg (Zastaprazan citrate 20 mg)

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

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

Preparation Example 4. Preparation of JP-1366 Capsules 20 mg (Zastaprazan Citrate 20 mg)

20 mg of zastaprazan citrate (azacyclobutane-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl} ketone citrate was obtained according to Preparation Example 1, and 181.4 mg of dextrorotatory mannitol, 12.4 mg of sodium cross-linked carboxymethyl cellulose, and 1.2 mg of magnesium stearate were mixed to obtain a mixture. This mixture was then filled into a No. 1 hard capsule, which was used as the capsule base, to prepare a capsule formulation.

The capsule preparation made in this way is called "JP-1366 Capsules 20 mg".

Preparation Example 5. JP-1366 Capsules 20 mg Placebo

Except for the absence of the main ingredient Zastaprazan citrate, the Zastaprazan 20 mg placebo capsules were prepared in the same manner as in Preparation Example 4. The capsule formulation prepared in this manner is called "JP-1366 Capsules 20 mg Placebo".

Example 1. In vitro efficacy trial against Helicobacter pylori

Experiments were conducted under in vitro experimental conditions to determine whether Zastaprazan has growth-inhibiting or urease-inhibiting effects on Helicobacter pylori.

1. Test material

A. Medicine

Table 1 shows the drugs used in the in vitro experiments.

[Table 1] medicine CAS number 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%

B. Reagent

Table 2 shows the reagents used in the in vitro experiments.

[Table 2] reagents CAS number Manufacturer Purity Brain Heart Infusion 237500 BD (Difco) N/A Muller-Hinton medium 275730 BD (Difco) N/A Bacto-agar 214010 BD (Difco) N/A Laked Horse Blood N/A Oxoid N/A Isovitalex N/A BD (BBL) N/A Horse serum N/A Sigma-Aldrich Heme, ≤20 mg/dL CampyGen N/A Oxoid N/A

C. strain

Helicobacter pylori (ATCC43504): A typical strain used for antibiotic susceptibility testing according to the Clinical and Laboratory Standards Institute (CLSI) guidelines.

Helicobacter pylori 26695 (ATCC700329): A strain isolated from a British patient known to have a history of gastric cancer development. This strain is positive for both CagA (cytotoxin-associated gene) and VacA (vacuole-associated cytotoxin), and has a well-known genetic background, therefore it is primarily intended for research purposes.

Helicobacter pylori SS1 (mouse colonizing strain): This strain is also known as the Sydney strain. It is CagA and VacA positive and has been shown to infect and colonize C57BL/6 mice. This strain is used for animal testing.

D. Instruments

Table 3 shows the instruments used in the in vitro experiments.

[Table 3] equipment Manufacturer Specifications 37℃ incubator Visionbionex Vision/VS-1203P3V Miniature centrifuge Gyrozen 1730R Spectrophotometer BIO-RAD BR170-2525 Microplate reader Molecular Devices SpectraMaxABS

2. Culture medium preparation

A. Culture medium

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% bacterial agar (Difco Inc., Sparks, MD, USA) to BHI.

B. Culture medium used to measure minimum inhibitory concentration (MIC)

The culture medium was prepared using Müller-Hinton medium (MH, Difco Inc., Sparks, MD, USA) [containing 7% differentiation medium (Sigma CO., LTD., St. Louis, USA) and 0.4% Isovitalex (BBL Inc., Sparks, MD, USA)].

3. In vitro efficacy test - MIC and minimum bactericidal concentration (MBC) of zastaprazan (JP-1366) against Helicobacter pylori.

(1) Method

Antibiotic susceptibility testing was performed using the microdilution method according to CLSI guidelines. A double-dilution was performed in 12 steps in 48-well plates, with a maximum concentration of 128 μg/mL for amoxicillin and clarithromycin, and 256 μg/mL for omeprazole. Bacteria were inoculated into wells containing only culture medium without antibiotics to prepare a positive control group, while wells containing only culture medium without antibiotics or uninoculated bacteria served as a negative control group. Preliminary experiments were conducted to determine the concentration range of the test substance zastaprazan (JP-1366) and non-surazine. Helicobacter pylori stored in an ultra-low temperature freezer (-70°C or lower) was thawed and inoculated onto BHI agar (containing 7% lysed horse blood and 0.4% Isovitalex). The cultures were incubated at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 for three days, and then transferred to fresh medium. The cultured bacteria were harvested, suspended in PBS, and inoculated into each well at a concentration of 5 × 10⁵ cfu/mL. The cultures were then incubated at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 for three days. The lowest concentration at which no bacterial growth was observed was defined as the MIC. Subsequently, 10 μL of culture medium at different concentrations from each well was spotted onto antibiotic-free BHI agar (containing 7% lysed horse blood and 0.4% isovitalex) and incubated at 37°C under microaerophilic conditions for three days. The lowest concentration at which no bacterial growth occurred was defined as MBC.

(2) Experimental Results and Analysis

To determine the MIC, visual inspection and absorbance measurement at 600 nm were performed, and bacterial growth was confirmed based on the absorbance of the negative control group containing only culture medium. To determine the MBC, after MIC determination, 10 μl of culture medium from each well was spotted onto solid culture medium without antibiotics or test substances, and bacterial growth was examined.

Regarding the suitability of the system in this test, quality control was performed based on the MIC value of amoxicillin against the typical strain H. pylori ATCC43504.

All tests were repeated, and the results were determined by repeating the experiment three times.

Referring to Table 4 below, the low solubility of zastaprazan (JP-1366) makes MIC analysis difficult (poor solubility, formation of suspension, interference with visual/absorbance analysis). Therefore, the MBC index is used to confirm the inhibitory effect on Helicobacter pylori strains.

It has been confirmed that the test substance Zastaprazan (JP-1366) is at least 2 times, and up to 16 times, better than omeprazole and non-surazine in inhibiting three strains of Helicobacter pylori in terms of MBC.

[Table 4] strain JP1366 Amoxicillin Clarithromycin Omeprazole non-Surazan MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC 43504 nd 8~32 0.016~0.032 0.032 0.032 0.063 32 64 64 64~128 26695 nd 16~32 0.016~0.032 0.032 0.063~0.125 0.125 32~64 64~128 64 64~128 SS1 nd 16~32 0.125~0.25 0.25 0.032 0.125 32~64 64~128 64 64~128

Example 2. Efficacy testing of anti-Helicobacter pylori in patients with erosive gastroesophageal reflux disease (Phase II clinical trial)

1. Individual Choice

Helicobacter pylori test

Helicobacter pylori testing was performed using the 13C-urea breath test (13C-UBT), gastroscopy (CLO biopsy), or tissue biopsy to confirm a positive/negative result for Helicobacter pylori. This test was performed at either the screening visit (Visit 1) or the random visit (Visit 2), and results from the same institution could be substituted within 29 days prior to the random visit (Visit 2).

Inclusion criteria

Unless otherwise specified, individuals must meet all of the following inclusion criteria to participate in this clinical trial.

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

2) Individuals who experienced heartburn or acid reflux symptoms within seven days prior to the screening visit (Visit 1). Heartburn ● Heartburn or burning sensation inside the sternum ● Pain inside the sternum ● Stabbing or burning sensation in the upper central abdomen (solar plexus) ● Pain in the upper central abdomen (solar plexus) Acid reflux ●Acid reflux (stomach acid)●Symptoms of stomach contents (stomach acid or food) flowing back up through the esophagus

3) Individuals diagnosed with erosive gastroesophageal reflux disease (GERD) of grade A or higher according to the Los Angeles Classification of Gastroesophageal Reflux Disease (GADS) by upper gastrointestinal endoscopy at the same institution within 29 days prior to random visits (Visit 2). LA rating standard A One or more esophageal mucosal lesions, with a length <5mm B One or more esophageal mucosal lesions, with a length ≥5mm. C The esophageal mucosal damage is continuous, but involves less than or equal to 75% of the esophageal circumference. D Esophageal mucosal damage involves at least 75% of the esophageal circumference.

4) Able to complete questionnaires and personal logs

5) Those who voluntarily give written consent to participate in this clinical trial

Exclusion criteria

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

1) Rule out disease

(1) During screening visits (visit 1), patients were found to have a Barrett's esophagus longer than 3 cm or significant developmental abnormalities by upper gastrointestinal endoscopy.

(2) Eosinophilic esophagitis (those with negative results in esophageal biopsy can be included.)

(3) Individuals with primary esophageal motility disorders or esophageal stenosis.

(4) Gastroesophageal varices

(5) During screening visits (visit 1), patients diagnosed with gastrointestinal bleeding or other abnormal bleeding are identified by upper gastrointestinal endoscopy.

(6) Those who have undergone gastric acid secretion suppression surgery or gastric or esophageal surgery. However, those who meet the following criteria may be included.

① Appendectomy, cholecystectomy, polyp removal

② Endoscopic resection of malignant tumors or endoscopic resection of early gastric cancer (endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD)) that have been cured and have not recurred for more than five years from the date of diagnosis.

(7) Individuals with active duodenal ulcers, gastric ulcers, or pancreatitis.

(8) Zollinger-Ellison syndrome

(9) Individuals with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD)

(10) Individuals with warning symptoms (such as dysphagia, severe dysphagia, bleeding, weight loss, anemia, or bloody stools) who are suspected of having a gastrointestinal malignancy by the investigator (however, those who test negative after confirming a tumor by upper gastrointestinal endoscopy may be included).

2) Medical history and complications

(1) Those with clinically significant diseases of the liver, kidneys, nervous system, respiratory system, endocrine system, hematological tumors, cardiovascular system, or urinary system.

(2) Those with a history of malignant tumors within five years prior to the screening visit (visit 1) (However, those who have been cured and have not had a recurrence for more than 5 years from the date of diagnosis may be included, but those with a history of digestive system malignant tumors and have undergone tumor resection (e.g., gastrectomy, colon resection, etc.) and who do not fall under items (1) to (6) may not be included.)

(3) Individuals with a history of alcohol or drug abuse within the year prior to the screening visit (Visit 1).

(4) Individuals with a history of being diagnosed with human immunodeficiency virus (HIV)

(5) Individuals diagnosed with a mental illness that may affect the implementation of this clinical trial (such as schizophrenia or dementia).

3) Laboratory test results (during the screening visit)

(1) Individuals whose serum AST, ALT, ALP, γ-GT, or total bilirubin levels exceed twice the upper limit of normal.

(2) Individuals whose serum BUN or serum creatinine levels exceed twice the upper limit of normal.

(3) Active hepatitis B or C (those who test negative for the virus may be included).

4) History of medication use/treatment

(1) Those who are taking or are planning to take prohibited medications during this clinical trial.

5) Allergy history

(1) Patients who are allergic to or have a history of allergy to clinically experimental drugs, Nexium tablets (esomeprazole), benzimidazoles, penicillin antibiotics, or macrolide antibiotics.

6) Other

(1) Pregnant women, breastfeeding women, women who have tested positive for pregnancy, women of childbearing age, or men who plan to become pregnant during this clinical trial.

(2) Fertility-bearing female individuals and their female partners who have not undergone infertility surgery and do not agree to use the following contraceptive methods during this clinical trial.

(3) Individuals who have received other clinical trial drugs within one month prior to the screening visit (Visit 1).

(4) Other than those mentioned above, the researchers determined that the participants were not suitable to participate in this clinical trial.

2. Clinical trial methods

This is a randomized, double-blind, active-controlled, multicenter phase 2 clinical trial in patients with erosive gastroesophageal reflux disease (GERD). Screening tests were conducted after individuals gave written consent to participate in this clinical trial. If individuals were taking medications that might affect the gastric mucosa at the time of screening, an upper gastrointestinal endoscopy was performed after a 2-week withdrawal period (4 weeks for potassium-competitive acid blockers (P-CABs) or proton pump inhibitors (PPIs)). Individuals 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. At this point, individuals were stratified according to the LA classification system, which classifies patients based on upper gastrointestinal endoscopy (A, B, C, D). Randomized individuals received the clinical trial drug once daily for four weeks, according to their assigned treatment group. Four weeks after starting the clinical trial drug, these individuals underwent upper gastrointestinal endoscopy at the clinical trial facility to assess their treatment status. Treated individuals underwent safety follow-up (F/U) two weeks later, while untreated individuals received the clinical trial drug for another four weeks (a total of eight weeks) and underwent upper gastrointestinal endoscopy at the clinical trial facility. Regardless of whether the condition is cured, a safety follow-up will be conducted two weeks later.

3. Dosage, administration time, and administration method

A. Dosage

- Test drug 1: JP-1366 5 mg 2 capsules (Zastaprazan citrate 10 mg)

- Test drug 2: JP-1366 20 mg per capsule (Zastaprazan citrate 20 mg)

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

B. Investment Period

Trial period for each individual: up to 14 weeks

- Screening period: 15 days or 29 days

- Investment period: 4 weeks (or 8 weeks)

- Safety follow-up period: 2 weeks after the last administration of the clinical trial drug.

C. Distribution Method

Based on the randomly assigned drug administration group, individuals will receive the clinical trial drug orally once daily at fixed intervals on an empty stomach for four weeks (or eight weeks*) starting from the date of drug provision.

*An additional four-week administration period will be given only to individuals whose mucosal lesions have not healed after four weeks of administration of the experimental drug in clinical trials.

4. Therapeutic endpoint

A. Primary therapeutic endpoint:

Cumulative healing rate (%) of mucosal damage from the time of drug administration to week 8 in clinical trials.

*The results of the upper gastrointestinal endoscopy showed that the eroded mucosa had returned to normal.

B. Secondary therapeutic endpoints:

① Mucosal lesion healing rate (%) from the time of drug administration in the clinical trial to week 4.

② Symptom assessment through individual logs

A. Assessment 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) for seven consecutive days after administration of the investigational drug in clinical trials.

C. The number of days to achieve complete remission (CR, disappearance of heartburn and acid reflux for seven days) after administration of the clinical trial drug.

D. The proportion of symptom-free days (heartburn, acid reflux, heartburn/acid reflux) lasting 4 weeks and 8 weeks after (daytime, nighttime, daytime/nighttime) clinical trial drug administration.

③ Changes in the frequency and severity of major symptoms at weeks 4 and 8 of clinical trial drug administration compared to the baseline of the Gastroesophageal Reflux Disease Questionnaire (RDQ).

④ Changes in total score compared to the GERD Health-Related Life Quality (GERD-HRQL) baseline at weeks 4 and 8 of clinical trial drug administration.

5. Safety endpoint

(1) Adverse reactions

(2) Vital signs

(3) Laboratory testing

(4) Electrocardiogram (12-lead ECG)

(5) Physical examination

6. Statistical Analysis Methods

A. Primary therapeutic endpoint

Cumulative healing rate (%) of mucosal damage from the time of drug administration to week 8 in clinical trials.

The proportion of individuals whose erosions returned to normal mucosa from the first administration of the clinical trial drug to week 8, and the bilateral 95% confidence intervals, were presented in the drug administration groups. To compare each test group with the control group (JP-1366 10 mg vs Nexium tablet 40 mg, JP-1366 20 mg vs Nexium tablet 40 mg), the Cochran-Mantel-Haenszel method, corrected for baseline LA grading (A, B, C, D) as the stratification factor, was used to obtain the lower limit of each bilateral 95% confidence interval.

B. Secondary therapeutic endpoints

① Mucosal lesion healing rate (%) from the time of drug administration in the clinical trial to week 4.

The percentage of individuals whose erosions returned to normal mucosa from the first administration of the clinical trial drug to week 4, and the bilateral 95% confidence intervals, were presented for each treatment group. To compare each test group with the control group (JP-1366 10 mg vs Nexium tablet 40 mg, JP-1366 20 mg vs Nexium tablet 40 mg), the Cochran-Mantel-Haenszel method, corrected for baseline LA grading (A, B, C, D) as the stratification factor, was used to obtain the lower limit of each bilateral 95% confidence interval.

② Symptom assessment through individual logs

A. Assessment of symptoms (heartburn, acid reflux, heartburn/acid reflux) within 24 hours after administration of the investigational drug: An ANCOVA model was used to analyze the mean assessments of symptoms (heartburn, acid reflux, heartburn/acid reflux) within 24 hours after the first administration of the investigational drug between the test and control groups using baseline LA rank (A, B, C, D) as covariates.

B. Assessment of symptoms (heartburn, acid reflux, heartburn/acid reflux) for seven consecutive days after administration of the investigational drug: The ANCOVA model was used to analyze the mean assessments of symptoms (heartburn, acid reflux, heartburn/acid reflux) for seven consecutive days after the first administration of the investigational drug between the test group and the control group using baseline LA gradations (A, B, C, D) as covariates.

C. Number of days to achieve CR (relief of heartburn and acid reflux for 7 days) after administration of the investigational drug: CR (relief of heartburn and acid reflux for 7 days) was defined as a symptom score of 0 for 7 consecutive days after the first administration of the investigational drug, and this event was based on the first CR. The absence of CR was considered censoring. Kaplan-Meier curves and medians were presented for each drug group, along with their two-sided 95% confidence intervals. A stratified log-rank test, corrected for baseline LA rank as the stratification factor, was used to analyze the comparison between the test and control groups.

D. The proportion of symptom-free days (heartburn, acid reflux, heartburn/acid reflux) for 4 and 8 weeks after administration of the investigational drug at (daytime, nighttime, and daytime/nighttime): The ANCOVA model was used to analyze the proportion of symptom-free days (heartburn, acid reflux, heartburn/acid reflux) for 4 and 8 weeks after the first administration of the investigational drug at (daytime, nighttime, and daytime/nighttime) in each test group and control group using baseline LA rank (A, B, C, D) as covariates.

③ The ANCOVA model was used with baseline LA gradations (A, B, C, D) as covariates to analyze the changes in the frequency and severity of major symptoms in each test group and control group at weeks 4 and 8 of the clinical trial compared to the gastroesophageal RDQ baseline. Changes in the final results (excluding baselines compared to the baseline) were subjected to the same statistical analysis as described above.

④ The ANCOVA model was used to analyze the changes in total scores of the test group and the control group at weeks 4 and 8 of the clinical trial compared with the baseline of the Quality of Life Assessment (GERD-HRQL) using the baseline LA grading (A, B, C, D) as covariates. The changes in the final results (excluding the baseline compared with the baseline) were subjected to the same statistical analysis as above.

C. Safety endpoint

For individuals who experienced at least one adverse reaction (or adverse drug reaction), the frequency and incidence of the reaction were presented in each dosing group, along with their two-sided 95% confidence intervals. A chi-square test or Fisher's exact test was performed to test for differences in the incidence of adverse reactions (or adverse drug reactions) between the control and test groups. Furthermore, the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) was used to present data coded by System Organ Class (SOC) and Preferred Term (PT). Serious adverse reactions, adverse reactions leading to discontinuation of the investigational drug, and adverse reactions leading to death were also summarized as SOC and PT using the latest version of MedDRA. For laboratory tests, vital signs, and electrocardiograms (12-lead ECGs), explanatory statistics (number of individuals, mean, standard deviation, median, minimum, maximum), changes at each visit, and changes relative to baseline were presented as continuous data, and contingency tables were created for categorical data. For laboratory tests and electrocardiograms (12-lead ECGs), changes relative to baseline after clinical trial drug administration were summarized in offset tables at each assessment time point and categorized as normal or clinically insignificant abnormalities (Normal or Abnormal NCS) and clinically significant abnormalities (Abnormal CS). This is a list of individuals whose physical examinations revealed normal baseline or clinically insignificant abnormalities (NCS) but who developed clinically significant abnormalities (CS) after administration of the clinical trial drug.

7. Results of Phase 2 Clinical Trial

A. Confirmation of symptom improvement

In the evaluation of all symptoms (heartburn, acid reflux, heartburn/acid reflux) within 24 hours and for 7 days following administration of the investigational drugs in the clinical trial, it was confirmed that all symptoms showed a trend of improvement within 24 hours and for 7 days following administration of test drugs 1 and 2, which were the investigational drugs in the clinical trial.

B. Cure rate confirmation

(1) Helicobacter pylori positive group (infection group)

The JP-1366 20 mg (Zastaprazan 20 mg) group showed 100% efficacy at both weeks 4 and 8, but the Nexium 40 mg group showed 87.5% efficacy (see Table 5).

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

(2) Helicobacter pylori negative group

The JP-1366 20 mg (Zastaprazan 20 mg) dosing group was confirmed to have the same effect as the Nexium 40 mg control group (see Table 6). Thus, it has been clinically confirmed that zastaprazan can produce the same effect as the Nexium 40 mg control group even at significantly lower doses.

[Table 6] JP-1366 10 mg (N=41) JP-1366 20 mg (N=42) Esomeprazole 40 mg (N=41) Healing rate in week 4 Cure rate, n (%) 39(95.12) 38 (90.48) 37 (90.24) Healing rate at week 8 Cure rate, n (%) 40 (97.56) 41 (97.62) 40 (97.56)

(3) Overall cure rate

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 proportion of individuals with complete healing of mucosal damage at week 4 after administration of the clinical trial drug was 93.75% (45/48 people) in the JP-13669 20 mg group, 44/49 people in the JP-13669 20 mg group, and 89.80% (44/49 people) in the esomeprazole 40 mg group.

(4) Conclusion

Nexium 40 mg showed a higher erosion healing rate in Helicobacter pylori-negative patients than in Helicobacter pylori-positive patients. However, the pharmaceutical composition of this invention exhibits therapeutic effects on gastroesophageal reflux disease and/or peptic ulcers regardless of Helicobacter pylori infection, and shows a trend towards higher efficacy in patients with Helicobacter pylori infection. This is due to the bacterial eradication effect of Zastaprazan itself contained in the pharmaceutical composition of this invention.

Example 3. Efficacy test of anti-Helicobacter pylori in patients with erosive gastroesophageal reflux disease (Phase 3 clinical trial)

1. Individual Choice

Helicobacter pylori test

Helicobacter pylori testing was performed via 13C-UBT, gastroscopy (CLO), or tissue biopsy to confirm a positive/negative H. pylori result. The test was performed at either a screening visit (Visit 1) or a random visit (Visit 2), and results from the same institution could be substituted within 29 days prior to the random visit (Visit 2).

Inclusion criteria

Unless otherwise specified, individuals must meet all of the following inclusion criteria to participate in this clinical trial.

1. Adult males and females who are 19 years of age or older as of the date of written consent.

2. Those who have experienced heartburn or acid reflux symptoms within seven days prior to the screening visit, and whose symptoms are severe and frequent enough to meet either 1) or 2) below:

1) Those who experience mild or more severe heartburn or acid reflux two or more times per week

2) Those who experience moderate or more severe heartburn or acid reflux once or more per week

3. Individuals diagnosed with erosive gastroesophageal reflux disease (GERD) of grade A or higher according to the Los Angeles Classification† via endoscopic examination within 15 days prior to randomization.

†Los Angeles Classification Classification Endoscopic examination results A One or more mucosal lesions not exceeding 5 mm in length and not extending between the apexes of two mucosal folds. B One or more mucosal tears exceeding 5 mm, but not extending to the apex of two mucosal folds. C One (or more) mucosal lesions are continuous between the apexes of two or more mucosal folds, but involve less than 75% of the circumference. D One or more mucosal lesions involving at least 75% of the esophageal circumference.

4. Those who fully understand this clinical trial and voluntarily give written consent to participate in this clinical trial.

Exclusion criteria

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

These individuals must not meet any of the following criteria.

1. Those who cannot undergo endoscopic examination

2. Medical History

1) Individuals with warning symptoms that may suggest a gastrointestinal malignancy (e.g., dysphagia, severe dysphagia, bleeding, weight loss, anemia, bloody stools) (however, those who test negative after confirming a malignancy by endoscopy can be excluded.)

2) Patients with eosinophilic esophagitis (those with negative esophageal biopsy results can be excluded).

3) Patients diagnosed with gastroesophageal stricture, gastroesophageal varices, Barrett's esophagus, active peptic ulcer, gastrointestinal bleeding, or gastrointestinal malignancies by endoscopy.

4) Patients with Zollinger-Ellison syndrome

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

6) Patients who have undergone gastric acid secretion suppression surgery or gastric or esophageal surgery (however, those with a history of appendectomy, cholecystectomy, or polyp removal may be excluded).

7) Patients with clinically significant diseases such as liver, kidney, cardiovascular, respiratory, endocrine, urinary, neurological, and hematological disorders.

8) Individuals with a history of malignant tumors within the 5 years prior to the screening period (however, regardless of the period, individuals with a history of gastrointestinal malignant tumors are excluded.)

3. The following abnormalities were observed during laboratory testing conducted during the screening process:

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 (Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation)

5) Positive serum test results (HBsAg, HCV Ab, HIV Ab, syphilis reaction test)

6) Individuals whose electrocardiogram (ECG) shows clinically significant abnormalities.

4. Allergic reactions and drug allergic reactions

1) Known allergic reaction to any component or additive in the clinical trial drug.

2) Individuals with clinically significant allergic diseases (excluding mild allergic rhinitis that does not require medication) or a history of allergic reactions to other medications (aspirin, antibiotics, etc.).

5. Contraindicated drugs and treatments

1) Individuals who have taken acid secretion inhibitors such as P-CAB or PPIs within two weeks prior to the endoscopic examination during screening.

2) Individuals who have taken two or more doses of reflux esophagitis-related medications (antacids, prokinetics, histamine 2-receptor antagonists) within one week prior to the endoscopy examination at the time of screening.

3) Patients who are unable to discontinue medications that may cause ulcers, such as aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), during clinical trials.

4) Individuals currently taking or requiring contraindication medications during this clinical trial. However, individuals already taking contraindication medications may participate after a two-week washout period. When the period corresponding to five times the half-life of the contraindication medication exceeds two weeks, the washout period should be five times the half-life of that medication.

6. Pregnant and breastfeeding women

7. Individuals and their partners (or spouses) who did not use medically acceptable contraception throughout the entire clinical trial.

1) Use an intrauterine contraceptive device with a proven pregnancy failure rate.

2) Use double-barrier contraception (male condom and diaphragm cap, diaphragm or cervical cap) and simultaneously administer spermicide.

3) Infertility management (vasectomy, salpingectomy and tubal ligation, hysterectomy)

8. Individuals with a clinically significant history of mental illness, drug abuse, or alcoholism.

9. Other than those mentioned above, participants deemed unsuitable to participate in this clinical trial by the researchers.

2. Clinical trial methods

Voluntary participants in this clinical trial underwent screening interviews, and only those meeting the inclusion/exclusion criteria were allowed to participate. Eligible individuals were randomly assigned to either the test or control group and received the investigational drug at the baseline interview (V2) according to their assigned group. During the total four-week treatment period, interviews were conducted on day 1 and week 4, with the investigational drug administered orally once daily.

3. Dosage, administration time, and administration method

A. Dosage

- Test drug: JP-1366 20 mg per capsule (Zastaprazan citrate 20 mg)

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

B. Investment period

Approximately 12 weeks (±14 days)

1. Screening period: up to two weeks from the first administration of the clinical trial drug.

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

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

C. Distribution Method

– The clinical trial drug was administered orally once daily for four weeks to randomly assigned groups, and at a fixed time of day whenever possible, regardless of meals. Drug administration group Clinical trial drugs 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

4. Accompanying medications

A. Contraindicated accompanying medications

The following drugs are contraindicated during this clinical trial.

1. All gastric acid secretion inhibitors other than the drug in this clinical trial.

2. Gastric mucosa protectant

3. Antacids

4. Prokinetic agents

5. Other gastrointestinal medications

6. Steroid preparations (However, topical, epidural, and inhalation administration are permitted.)

7. NSAIDs (However, short-term use of NSAIDs for the treatment of acute pain is permissible according to investigators' judgment.)

8. Cholinesterols, antipsychotics, and antithrombotic drugs (anticoagulants or antiplatelet agents (including aspirin)).

9. Drugs known to interact with the investigational drug in this clinical trial.

B. Accompanying medications

1. Medications administered to treat comorbidities may continue to be used without changing the administration method and dosage. However, if it is determined that the medication administered to treat comorbidities will not affect this clinical trial, changes to the administration and dosage may be made. Other medications may be administered concurrently if they are determined not to affect this clinical trial.

2. Medication may be used for endoscopic examinations and pretreatment of UBT.

5. Results of Phase 3 Clinical Trial

A. Confirmation of mucosal damage healing rate

(1) Confirmation of the cumulative healing rate of mucosal lesions in individuals who tested positive for Helicobacter pylori.

The cumulative healing rate of mucosal damage with or without Helicobacter pylori infection refers to the proportion of individuals whose mucosal damage has been confirmed to have healed by endoscopy within 4 weeks after administration of the clinical trial drug.

Based on the presence or absence of Helicobacter pylori infection, the frequency and percentage of mucosal lesion healing at week 4 after administration of the investigational drug were presented in each treatment group. Differences between treatment groups (test group vs. control group) were analyzed using the Cochran-Mantel-Haenszel method, corrected for the baseline LA classification method as the stratification factor, and 95% confidence intervals for these differences are presented.

According to the protocol set (PPS)

According to the PPS analysis results of the primary analysis group in this clinical trial, the number of individuals testing positive for Helicobacter pylori was 26 in the test group and 22 in the control group. In the endoscopic examination at week 4 after administration of the investigational drug, the proportion of individuals with healed mucosal lesions was 100.00% (26/26) in the test group and 81.82% (18/22) in the control group, showing a statistically significant difference between the two groups (p=0.0214).

Full Analysis Set (FAS)

According to the FAS analysis, the number of individuals testing positive for Helicobacter pylori was 28 in the test group and 25 in the control group. At week 4 after administration of the investigational drug, the percentage of individuals with healed mucosal lesions on endoscopic examination was 96.43% (27/28 individuals) in the test group and 80.00% (20/25 individuals) in the control group. The test group showed excellent results at week 4 and was significantly different from the control group.

[Table 7] JP-1366 20 mg Esomeprazole 40 mg Number of individuals 26 twenty two The number of individuals cured, n (%) 26 (100.00) 18(81.82)

[Table 8] JP-1366 20 mg Esomeprazole 40 mg Number of individuals 28 25 The number of individuals cured, n (%) 27 (96.43) (80.00)

Although specific aspects of the invention have been described in detail above, it will be apparent to those skilled in the art that these descriptions are merely preferred embodiments, and the scope of the invention is not limited thereto. Therefore, the actual scope of the invention will be defined by the appended patent claims and their equivalents.

without

without

Claims (7)

A composition for the eradication of Helicobacter pylori comprising Zastaprazan, its pharmaceutically acceptable salt, its hydrate or solvent, or a mixture thereof. The composition for Helicobacter pylori eradication as described in claim 1, wherein the pharmaceutically acceptable salt of Zastaprazan is Zastaprazan citrate. The composition for Helicobacter pylori eradication as described in claim 1, wherein the composition for eradication comprises a pharmaceutically acceptable salt of Zastaprazan in a dose of 10 mg, 20 mg or 40 mg. The composition for Helicobacter pylori eradication as described in claim 1, wherein the composition for eradication is administered once to three times daily. The composition for Helicobacter pylori eradication as described in claim 1, wherein the composition for eradication is administered once daily. The composition for Helicobacter pylori eradication as described in claim 1, wherein the composition for eradication is formulated as a solid oral preparation. The composition for Helicobacter pylori eradication as described in claim 6, wherein the solid oral preparation is any one of tablets, film-coated tablets, capsules, powders, granules, pills, throat lozenges, oral jelly, and orally disintegrating film preparations.