COMPOSITION TO ERADICATE HELICOBACTER PYLORI

Abstract

The present invention relates to a composition for eradicating Helicobacter pylori and its use. The composition of the present invention maintains an intragastric pH at a certain level or higher for a certain period of time or longer, thereby maximizing the action of amoxicillin and clarithromycin to show an excellent effect on the eradication of Helicobacter pylori.

Description

COMPOSITION TO ERADICATE HELICOBACTER PYLORI FIELD OF INVENTION The present invention relates to a composition for eradicating Helicobacter pylori and its use. BACKGROUND OF THE INVENTION Helicobacter pylori (HP bacteria, H. pylori), which is a bacterium involved in the appearance of various gastrointestinal disorders such as gastritis, ulcers, etc., causes serious damage to human health. Helicobacter pylori reproduces in the gastric mucosa of humans. It is a known pathogen that causes gastritis, gastric ulcers, and duodenal ulcers, and is also associated with diseases such as gastric mucosa-associated lymphoid tissue (MALT) lymphomas, atrophic gastritis, and gastric hyperplastic polyps. Once Helicobacter pylori is deposited in the gastric mucosa, it is not eliminated but continues to reproduce in the stomach despite strong immune responses to infection. Furthermore, the pH in the stomach remains very low due to hydrochloric acid, rendering many antibiotics ineffective. Currently, a triple combination therapy with antibiotics (amoxicillin and clarithromycin) and a proton pump inhibitor is known to be partially effective in eradicating Helicobacter pylori. However, with the emergence of antibiotic-resistant bacteria, achieving complete eradication with this method has become difficult. For example, the success rate for Helicobacter pylori eradication has recently declined to 80% or less worldwide, and even to 70% or less in some countries. Studies conducted in South Korea over the past five years, from 2011 to 2015, also found that the Helicobacter pylori eradication rate fell to 70.7% (58.7–80.0%) in an intention-to-treat (ITT) analysis and to 76.2% (64.5–87.5%) in a per-protocol (PP) analysis. One factor contributing to this decline in the eradication rate is the increasing resistance of Helicobacter pylori to antibiotics used therapeutically. In particular, its growing resistance to clarithromycin is becoming a key factor in the failure of standard triple therapy. Therefore, second-line, third-line, etc. eradication therapies have been used., based on new antibiotics (metronidazole and levofloxacin) but with many limitations, also because such eradication methods also influence the action of beneficial enterobacteria in the human body, thus causing a problem of side effects such as diarrhea, etc. As discussed earlier, prolonged antibiotic use raises serious concerns about the development of resistant bacteria. Specifically, the prevalence of clarithromycin-resistant bacteria tends to increase rapidly. In one example of infections with resistant bacteria, eradication rates have been reported to decline significantly, and clarithromycin resistance has been acquired after failed eradication attempts. In other words, inadequate eradication treatment, when performed carelessly, is believed to have increased the emergence of resistant bacteria. Therefore, providing an optimal environment sufficient for effective eradication treatment is crucial. Another important factor in eradication therapy is maintaining an intragastric pH of at least 5, which optimizes the action of antibiotics. Intragastric pH has been reported to be 5.0–7.6 for 24 hours in patients in whom eradication therapy has been successful, while it is 2.2–6.2 in cases where it has failed. Therefore, this report indicates that maintaining a high pH in the stomach is crucial for successful eradication therapy. In other words, there is a need to develop and use a drug that can inhibit gastric acid secretion for a period of time appropriate to raise the pH close to a unique pKa value for antibiotics, thereby increasing the stability of the antibiotics and reducing the minimum inhibitory concentration of the antibiotics in Helicobacter pylori. either? zznn / Lznz / E / YiAi BRIEF DESCRIPTION OF THE INVENTION Technical problem In this context, the present inventors have made every effort to develop a suitable composition for eradicating Helicobacter pylori, and have therefore identified that a certain benzimidazole-derived compound exhibits an excellent effect on pH growth in the stomach and has a remarkable effect on the eradication of Helicobacter pylori when used in conjunction with amoxicillin and clarithromycin, thus completing the present invention. The present invention provides a pharmaceutical composition for eradicating Helicobacter pylori, comprising: a compound represented by the following formula 1, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or pharmaceutically acceptable salts thereof; and clarithromycin or pharmaceutically acceptable salts thereof as the active ingredient: Formula 1 or? zznn / Lznz / E / YiAi The present invention provides a combination containing: a compound represented by Formula 1 above, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or pharmaceutically acceptable salts thereof; and clarithromycin or pharmaceutically acceptable salts thereof. The present invention provides a kit that includes a combination containing: a compound represented by the above formula 1, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts. The present invention provides a method for eradicating Helicobacter pylori, which includes a step of administering a pharmaceutical composition containing: a compound represented by Formula 1 above, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts as an active ingredient, in subjects in need. The present invention provides a use of a compound represented by Formula 1 above, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts, in the preparation of a drug for eradicating Helicobacter pylori. The present invention provides a use of a compound represented by Formula 1 above, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts, in the eradication of Helicobacter pylori. ο / ζζηη / ίζηζ / Β / γι Technical solution The present invention provides a pharmaceutical composition for eradicating Helicobacter pylori, comprising: a compound represented by the following formula 1, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or pharmaceutically acceptable salts thereof; and clarithromycin or pharmaceutically acceptable salts thereof as the active ingredient: Formula 1 The compound represented by formula 1 above is also called 4(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide. This compound may be isolated from a natural source; it may be prepared by chemical modification after being obtained from the natural source; or it may be prepared by skilled personnel by chemical synthesis according to a known method of synthesis (International Patent Publication WO2007 / 072146). In addition, commercially manufactured products may be purchased and used as the compound. In the case of the compound represented by formula 1 above in the present invention, said compound or pharmaceutically acceptable salts thereof, as well as solvates, hydrates and stereoisomers, which may be prepared from it and have the same effectiveness, are included within the scope of the present invention. In particular, the compound represented by formula 1 above can be a compound represented by the following formula 2: either? zznn / Lznz / E / YiAi Formula 2 The pharmaceutical composition of the present invention may contain the compound represented by formula 1 above, optical isomers thereof, or pharmaceutically acceptable salts thereof in an amount of 10 to 500 mg, particularly in an amount of 30 to 200 mg, and more particularly in an amount of 100 to 200 mg, but is not limited to the same. Amoxicillin is named “(2S,5R,6R)-6-[(R)-2-amino-2-(4-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thio-1-azabicyclo[3.2.0]heptane-2-carboxylic acid” and has a structure of the following formula 3: qj zznn / Lznz / E / YiAi Formula 3 This compound can be isolated from a natural source; it can be prepared by chemical modification after being obtained from the natural source; or it can be prepared by skilled personnel through chemical synthesis according to a known method. In addition, commercially manufactured products can be purchased and used as the compound. In the case of the compound represented by formula 3 above in the present invention, said compound or pharmaceutically acceptable salts thereof, as well as solvates and hydrates, which may be prepared from it and have the same efficacy, are included within the scope of the present invention The pharmaceutical composition of the present invention may contain amoxicillin or its pharmaceutically acceptable salts in an amount of 100 mg to 4 g, particularly in an amount of 500 mg to 2.5 g, and more particularly in an amount of 1 g to 2 g, but not limited to the same. Clarithromycin is named (3R, 4S, 5S, 6R, 7R, 9R, 11R, 12R, 13S, 14R) 6-[(2S, 3R, 4S, 6R)-4-(dimethylamino)-3-hydroxy-6-methyloxane-2-yl]oxy-14-ethyl-12,13-dihydroxy-4-[(2R, 4R, 5S, 6S)-5-hydroxy-4-methoxy-4,6-dimethyloxane-2-yl]oxy-7-methoxy3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione” and has a structure of the following formula 4: Formula 4 or? zznn / Lznz / E / YiAi or This compound can be isolated from a natural source; it can be prepared by chemical modification after being obtained from the natural source; or it can be prepared by skilled personnel through chemical synthesis according to a known method. In addition, commercially manufactured products can be purchased and used as the compound. In the case of the compound represented by formula 4 above in the present invention, said compound or pharmaceutically acceptable salts thereof, as well as solvates and hydrates, which may be prepared from it and have the same efficacy, are included within the scope of the present invention The pharmaceutical composition of the present invention may contain clarithromycin or pharmaceutically acceptable salts thereof in amounts from 50 mg to 3 g, particularly from 100 mg to 1 g, and more particularly from 500 mg to 1 g, but is not limited to these amounts. In the present invention, pharmaceutically acceptable salts means salts formed with any inorganic acid, organic acid, or base that does not cause serious irritation to the organic bodies dosed with it, nor impair the biological activity and physical properties of the compound. The following salts may be used: salts conventionally used in the art, such as acid addition salts formed with pharmaceutically acceptable free acid. Helicobacter pylori is a bacterium identified as a pathogen causing chronic gastritis, gastric / duodenal ulcers, stomach cancer, and other conditions. It thrives in the gastric mucosa of the human body. As a gram-negative bacillus with multiple flagella, this bacterium proliferates on the surface or in the mucus of the gastric mucosa. Helicobacter pylori, a spiral-shaped, motile, gram-negative bacillus, lives in the mucus layer of the gastric mucosa and possesses an enzyme called urease to break down urea and produce ammonia. Helicobacter pylori uses this ammonia to neutralize the strong acidic environment in the stomach, allowing it to survive. It has recently been discovered that Helicobacter pylori is resistant to several antibiotics. For example, resistant strains can be defined by their minimum inhibitory concentration (MIC) values. The MIC represents the minimum concentration required for drugs, such as antibiotics, to inhibit bacterial growth. In particular, those strains that have a MIC value of 0.03 pg / ml or more, preferably 0.5 pg / ml or more with respect to amoxicillin, can be defined as amoxicillin-resistant strains. In particular, those strains that have an MIC value of 1 pg / ml or more, preferably 1.5 pg / ml or more with respect to clarithromycin, can be defined as clarithromycin-resistant strains. Antibiotic-resistant Helicobacter pylori means Helicobacter pylori that shows resistance to antibiotics due to the continued use of antibiotics or a variation of Helicobacter pylori itself. In the present invention, eradication includes the elimination of microorganisms from a location where they are present, or the inhibition of their proliferation and growth. In the present invention, the eradication of Helicobacter pylori includes the elimination of Helicobacter pylori present in the stomach or the inhibition of its proliferation and growth. The composition of the present invention shows an excellent effect in eradicating even antibiotic-resistant Helicobacter pylori and is therefore effectively used to eradicate resistant strains. In the present invention, prevention includes all acts of inhibition or 77nn / Lznz / E / YILI delaying the growth of Helicobacter pylori in advance with the administration of the composition of the present invention, while treatment includes all acts of eradicating Helicobacter pylori with the composition of the present invention, thereby improving or beneficially changing diseases such as chronic gastritis, gastric / duodenal ulcers, stomach cancer, etc., which occur due to Helicobacter pylori as the causative pathogen. The compound represented by Formula 1 of the present invention acts as a competitive potassium acid blocker (P-CAB) to maintain an intragastric pH of 5 or higher, particularly 5.5 or higher, and more specifically 6.0 or higher, such that the composition maintains a pH close to the pKa value of antibiotics, namely amoxicillin and clarithromycin, thereby improving the stability of the antibiotics and significantly reducing their minimum inhibitory concentration. Furthermore, this compound has a long half-life, allowing it to increase the intragastric pH for a certain period of time or longer, thus maximizing the eradication effect of amoxicillin and clarithromycin. When the Formula 1 compound of the present invention was administered with amoxicillin and clarithromycin in combination, the Cmax (maximum serum concentration) and AUC (area under the curve) of the Formula 1 compound and clarithromycin increased, and it was confirmed that the drug bioavailability had increased after administering three formulations in combination. Furthermore, this compound demonstrates excellent eradication properties, even for antibiotic-resistant Helicobacter pylori, and can therefore be used effectively to eliminate resistant strains. Additionally, it maintains the pH at a certain level or higher for an extended period, thus promoting improved medication adherence. In particular, in the case of the compound represented by formula 1 of the present invention, a percentage of time in which an intragastric pH is maintained at more than 5, particularly a percentage of time in which an intragastric pH is maintained at more than 5.5, and more particularly more than 6.0 for a period of up to 24 hours after administration thereof, is at least 60%, at least 70%, at least 80% and at least 90%, so that the compound maintains a high pH value for a long period of time and thereby maximizes the eradication effect of amoxicillin and clarithromycin. Furthermore, the compound represented by formula 1 of the present invention rapidly increases the intragastric pH to at least 5, at least 5.5, and at least 6.0 within 3 hours, particularly within 2.5 hours, and more particularly within 2 hours after administration thereof, thereby maximizing the eradication effect of amoxicillin and clarithromycin. A pharmaceutical composition containing: the compound represented by formula 1 of the present invention, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may further contain suitable carriers, excipients or diluents, which are conventionally used. The compound represented by formula 1, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may further contain suitable carriers, excipients or diluents, which are conventionally used by each of them, and may therefore be formulated into dosage forms. The compound represented by formula 1, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may further contain suitable carriers, excipients or diluents, which are conventionally used by at least two of them, and may therefore be formulated into dosage forms. The compound represented by formula 1, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may further contain suitable carriers, excipients or diluents, which are conventionally used together, and may therefore be formulated into a dosage form. either? zznn / Lznz / E / YiAi In the present invention, pharmaceutically acceptable carriers include carriers or diluents that do not irritate organisms or inhibit the biological activity and characteristics of an injected compound. The types of such carriers usable in the present invention are not particularly limited, and any carrier may be used, provided it is conventionally used in the art and pharmaceutically acceptable. Examples of such carriers, but not limited to, include saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, starch, lactose, mannitol, etc. These carriers may be used alone, or at least two of them may be mixed together. Furthermore, these carriers may be used with the addition of other conventional additives, such as antioxidants and / or buffer solutions, etc., if required. If the compound represented by formula 1 of the present invention, its optical isomers, or pharmaceutically acceptable salts thereof are formulated into a preparation, the carriers may be contained in an amount of 0.01 to 50.0% by weight, and particularly in an amount of 0.1 to 10% by weight with respect to the total weight of the preparation, but not limited to the same. If amoxicillin or its pharmaceutically acceptable salts are formulated in a preparation, the carriers may be contained in an amount of 0.01 to 50.0% by weight, and particularly in an amount of 0.1 to 10% by weight with respect to the total weight of the preparation, but not limited to the same. If clarithromycin or its pharmaceutically acceptable salts are formulated in a preparation, the carriers may be contained in an amount of 0.01 to 50.0% by weight, and particularly in an amount of 0.1 to 10% by weight with respect to the total weight of the preparation, but not limited to the same. In the present invention, administration means introducing the pharmaceutical composition of the present invention into the subjects concerned by any appropriate method, and such administration may be carried out via various oral or parenteral routes, provided that said composition can reach a target tissue. In particular, said composition may be administered via an oral route of administration, but is not limited to such routes. The compound represented by Formula 1, its optical isomers or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; or clarithromycin or its pharmaceutically acceptable salts thereof may be formulated respectively in a separate dosage form for administration. In the present invention, the frequency of administration of the compound represented by Formula 1, optical isomers thereof, or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may vary depending on several factors, including age, weight, sex, severity, and the administered dose. For example, such administration may be once a day, twice a day, three times a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.In particular, such administration is performed once a day or twice a day, and maintains an intragastric pH at a certain level or higher for a certain period of time or more within such administration frequency, thereby maintaining a pH close to a pKa value of amoxicillin and clarithromycin to enhance the stability of the antibiotics and thus greatly reduce a minimum inhibitory concentration of the antibiotics to maximize the eradication effect of amoxicillin and clarithromycin. In the present invention, said pharmaceutical composition can be administered to subjects infected with Helicobacter pylori, where said Helicobacter pylori may be resistant to antibiotics, and in particular may be resistant to amoxicillin or clarithromycin, but not limited to them. Furthermore, the present invention provides a method for eradicating Helicobacter pylori, which includes a step of administering said pharmaceutical composition to subjects who need it. This pharmaceutical composition can be administered in a pharmaceutically effective amount to eradicate Helicobacter pylori. This pharmaceutical composition can be administered alone or in combination with surgery. ΖΖΠΠ / ίΖΠΖ / Ε / ΥΙΛΙ endocrine therapy, chemotherapy and methods of using a biological response modifier. In the present invention, any subject may be treated without particular limitation, provided that eradication of Helicobacter pylori is required, and in particular that infection with Helicobacter pylori is suspected as the cause of chronic gastritis, gastric / duodenal ulcers, stomach cancer, etc. Specifically, such subjects include all animals, including humans and non-humans, such as monkeys, dogs, cats, rabbits, guinea pigs, rats, mice, cows, sheep, pigs, goats, etc., and may be effectively treated by administering the pharmaceutical composition containing the compound of the invention or pharmaceutically acceptable salts thereof to the subjects in question. The present invention provides a use of the compound represented by Formula 1 above, optical isomers thereof, or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts, in the preparation of a drug for eradicating Helicobacter pylori. To prepare a drug for eradicating Helicobacter pylori, the compound represented by Formula 1 above, or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared in complex formulations together with other active agents, thus having a synergistic effect of the active components. The present invention provides a use of the compound represented by Formula 1 above, optical isomers thereof, or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts, for the eradication of Helicobacter pylori. The compound represented by Formula 1 above, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared in complex preparations together with other active agents, thus having a synergistic action of the active components. The present invention provides a composition to be used for eradicating Helicobacter pylori, containing: the compound represented by formula 1 above, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts. The present invention provides a combination containing: the compound represented by formula 1 above, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts. In particular, the present invention provides a combination for eradicating Helicobacterpylori, containing: the compound represented by Formula 1 above, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts. In the present invention, the combination refers to any union between at least two preparations. The combination may consist of at least two separate preparations, mixtures thereof, or any modification thereof. In other words, the combination may contain each of the separate preparations and may be formed from one preparation. This combination can be packaged in a kit. The kit includes each of the preparations separately and may optionally include other items, such as additional reagents, user manuals, or similar materials. In other words, the present invention provides the kit that includes the combination to eradicate Helicobacter pylori, which contains: the compound represented by formula 1 above, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts. The substances mentioned in the composition of the present invention also apply equally to the combination, kit, therapeutic method and use, if they are not contradictory to each other. either? zznn / Lznz / E / YiAi Advantageous effects A pharmaceutical composition of the present invention maintains an intragastric pH at a certain level or higher for a certain period of time or longer, thereby maintaining a pH close to the pKa value of amoxicillin and clarithromycin to improve the stability of the antibiotics and thus greatly reduce the minimum inhibitory concentration of the antibiotics to maximize the eradication effect of amoxicillin and clarithromycin. Furthermore, this composition exhibits excellent eradication effectiveness against even antibiotic-resistant Helicobacter pylori and can therefore also be used effectively to eradicate resistant strains. This composition continues to maintain the pH at a certain level or higher for an extended period, thus providing the advantage of improved medication compliance.Furthermore, this composition has an advantage, as it can be available before or after meals without requiring dietary therapy, unlike existing combination therapies. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing a change in intragastric pH and percentage of time at pH 6 or higher in individuals on day 1 after administering the composition of the invention; and pantoprazole, amoxicillin, and clarithromycin as a control group in the individuals (a left circle refers to Tegoprazan 50 mg; a middle circle makes Tegoprazan 100 mg; and a right circle makes Pantoprazole 40 mg). Figure 2 is a graph showing a change in intragastric pH and percentage of time at pH 6 or higher in individuals on day 7 after administering the inventive composition; and pantoprazole, amoxicillin, and clarithromycin as a control group in individuals (a left circle refers to Tegoprazan 50 mg; a middle circle makes Tegoprazan 100 mg; and a right circle makes Pantoprazole 40 mg). DETAILED DESCRIPTION OF THE INVENTION Mode of invention The present invention will henceforth be described in more detail by means of exemplary embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present invention in more detail, and the scope of the present invention is therefore not limited to them. Example 1: CJ-12420 (Teqoprazan) 50 mg, amoxicillin and clarithromycin (1) Tablet containing 50 mg of CJ-12420 (Teqoprazan) A preparation was produced according to the following procedure to prepare 50 mg of CJ-12420. A dosage form was prepared to contain 50 mg of 4-[(5,7-difluoro-3,4-dihydro-2H-chromeno-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazol-6-carboxamide as the main component. Mannitol, microcrystalline cellulose, and croscarmellose sodium were blended into said main component, wherein the fillers were contained in a ratio of 1 to 99% (50 mg of mannitol and 80 mg of microcrystalline cellulose) with respect to the parts by weight of a final dosage form, and a proportion of disintegrants within a range of 1 to 20% (10 mg of croscarmellose sodium) with respect to the parts by weight of the final dosage form was used to prepare a mixture. A binding solution containing hydroxypropylcellulose and purified water was added to the resulting mixture, and it was subjected to granulation, in which a binder content within a range of 4 to 40% (6 mg of hydroxypropylcellulose) was used with respect to parts by weight of an active component to prepare granules. The granules underwent a drying process, after which they were ground, so that the resulting regulated size products, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate were added to the granules and mixed. A proportion of diluents within a range of 1 to 10% (2 mg of colloidal silicon dioxide) was used with respect to the parts by weight of the final dosage form, and a proportion of lubricant within a range of 1 to 10% (2 mg of magnesium stearate) was used with respect to the parts by weight of the final dosage form, after which the resulting mixture was compressed and prepared into a tablet. The tablet was coated with a film coating agent. The tablet was prepared such that the coating was formed in a weight ratio of 2 to 6% (6 mg) with respect to the weight parts of the final dosage form. (2) Amoxicillin or clarithromycin tablet For amoxicillin, 1000 mg Kymoxin® capsules from Yuhan Corp. were used, while for clarithromycin, 500 mg Klaricid® film-coated tablets from Abbott Korea Co., Ltd. were used. Example 2: CJ-12420 (Tegoprazan) 100 mg, amoxicillin and clarithromycin (1) Tablet containing 100 mg of CJ-12420 (Tegoprazan) A preparation was produced according to the following procedure to prepare 100 mg of CJ-12420. A dosage form was prepared to contain 100 mg of 4-[(5,7-difluoro-3,4-dihydro-2H-chromeno-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazol-6-carboxamide as the main component. Mannitol, microcrystalline cellulose, and croscarmellose sodium were blended into said main component, wherein the fillers were contained in a ratio of 1 to 99% (100 mg of mannitol and 160 mg of microcrystalline cellulose) with respect to the parts by weight of a final dosage form, and a proportion of disintegrants within a range of 1 to 20% (20 mg of croscarmellose sodium) with respect to the parts by weight of the final dosage form was used to prepare a mixture. A binding solution containing hydroxypropylcellulose and purified water was added to the resulting mixture, and it was subjected to granulation, in which a binder content within a range of 4 to 40% (12 mg of hydroxypropylcellulose) was used with respect to parts by weight of an active component to prepare granules. The granules underwent a drying process, after which they were ground, so that the resulting regulated size products, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate were added to the granules and mixed. A proportion of diluents within a range of 1 to 10% (4 mg of colloidal silicon dioxide) was used with respect to the parts by weight of a final dosage form, and a proportion of lubricant within a range of 1 to 10% (4 mg of magnesium stearate) was used with respect to the parts by weight of the final dosage form, after which the resulting mixture was compressed and prepared into a tablet. The tablet was coated with a film coating agent. The tablet was prepared such that the coating was formed in a weight ratio of 2 to 6% (12 mg) with respect to the weight parts of the final dosage form. (2) Amoxicillin or clarithromycin tablet For amoxicillin, 1000 mg Kymoxin® capsules from Yuhan Corp. were used, while for clarithromycin, 500 mg Klaricid® film-coated tablets from Abbott Korea Co., Ltd. were used. Comparative example 1: pantoprazole, amoxicillin, and clarithromycin 40 mg of Pantoloc® tablet from Takeda Pharmaceutical Co. Ltd. was used for pantoprazole; 1000 mg of Kymoxin® capsule from Yuhan Corp. was used for amoxicillin; and 500 mg of Klaricid® film-coated tablet from Abbott Korea Co., Ltd. was used for clarithromycin. Comparative example 2: lansoprazole, amoxicillin, and clarithromycin 30 mg of Lanston® capsules from Jeil Pharmaceutical Co., Ltd., were used for lansoprazole, 1000 mg of Kymoxin® capsules from Yuhan Corp., for amoxicillin, and 500 mg of Klaricid® film-coated tablet from Abbott Korea Co., Ltd., for clarithromycin. Example 3: Clinical Study 1 1. Selection of subjects (1) Cohort 1 To evaluate the pharmacokinetic interaction of single and combination multiple-dose administration of tegoprazan and amoxicillin / clarithromycin, a clinical study was designed according to a randomized, open-label, multiple-dose design. A total of 24 subjects who had been deemed eligible to participate in the study were randomly assigned in a 1:1 ratio to each of the two groups. Each randomized group was administered investigational medical products as prescribed during each intervention period and underwent a clinical study as designed. Taking into account the half-life of each product, a washout period of 14 days was provided between intervention periods. (2) Cohort 2 To identify a Helicobacter pylori eradication effect of the present invention, a clinical study was designed according to a randomized, open-label, active-controlled, parallel, multiple-dose design. A total of 221 patients were screened for this study. Of these, 36 patients were enrolled, and complete clinical results were obtained for 34 patients. In particular, the 36 previous patients were divided into three patient groups (T1, T2 and R) and the clinical study was conducted accordingly. either? zznn / Lznz / E / YiAi Table 1 T1 (N = 12) CJ-12420 50 mg + Amoxicillin 1000 mg / Clarithromycin 500 mg. Repeated administration twice daily for seven days. T2 (N = 12) CJ-12420 100 mg + Amoxicillin 1000 mg / Clarithromycin 500 mg. Repeated administration twice daily for seven days. R (N = 12) Pantoprazole 40 mg + Amoxicillin 1000 mg / Clarithromycin 500 mg. Repeated administration twice daily for seven days. Inclusion criteria Trial subjects must meet the following selection criteria to be eligible to participate in this clinical study, unless otherwise specified: 1) Healthy adults aged between 19 and 45 years inclusive at the time of the screening test; 2) Without congenital or chronic disease, and without morbid symptoms or detections in the examination; 3) Body mass index (BMI) between 18.5 and 28.0 kg / m2 inclusive; 4) Deemed eligible based on medical examinations (including interviews, vital signs, 12-lead ECG, physical examination, laboratory tests, etc.) that are established and performed by an investigator in accordance with the profiles of an investigational product; 5) Voluntary consent to participate in the entire clinical study process after being fully informed of the purpose and content of the study, the profiles of the investigational product, etc., prior to participation in this clinical study; and 6) Positive in the urea13C breath test. Exclusion criteria The subjects of the trial were excluded from this clinical study if any of the following occurred: 1) Medical history a) History or current evidence of diseases considered clinically relevant by the investigator, including liver, kidney, gastrointestinal, respiratory, musculoskeletal, endocrine, neuropsychiatric, hematological-oncological, urinary or cardiovascular diseases (including cardiac arrhythmia); b) History of gastrointestinal diseases (e.g., gastritis, gastrospasm, gastroesophageal reflux disease, Crohn's disease, ulcer, etc.) or abdominal surgery (except appendectomy or simple herniotomy) that the investigator considers to have a potential effect on drug absorption; and c) Failure of previous treatment for H. pylori eradication. 2) Laboratory tests and ECG a) the AST or ALT value is at least 1.25 times greater than the upper limit of normality (ULN); b) the total bilirubin value is 1.5 times higher than the ULN; c) eFGR calculated by the CKD-EPI formula is less than 80 ml / min; and d) any clinically relevant abnormality in the ECG. 3) Allergy and drug abuse a) History of hypersensitivity to this investigational product, components contained in the investigational product (penicillin, cefem and macrolide antibiotics, pantoprazole and benzimidazoles) and other drugs (including aspirin, antibiotics, etc.); and b) History of drug abuse or positive drug test. 4) Drug / dietary restrictions a) Drugs (including herbal supplements) or abnormal diets (e.g., ingesting at least 1 liter of grapefruit juice, excessive garlic, broccoli, kale, etc.), which may have an effect on the absorption, distribution, metabolism and excretion of the investigational product, within 28 days prior to the first study dose of the investigational product; b) Use of prescription drugs (PDTs), any over-the-counter (OTC) drugs, vitamins or similar substances within 10 days prior to the first study dose of the investigational product; and c) Participate in other clinical studies to receive other investigational products within three months prior to the first study dose of the investigational product (except for not taking the investigational products). 5) Blood donation and transfusion a) Donation of whole blood within 60 days prior to the first study dose of the investigational product; and b) Donation and transfusion of blood components within 30 days prior to the first study dose of the investigational product. EITHER? ΖΖΠΠ / ίΖΠΖ / Ε / ΥΙΛΙ 6) Pregnancy and contraception a) Pregnant, positive in the pregnancy test or breastfeeding; and b) The subject's or his or her spouse or partner's inability to use medically qualified dual contraceptive methods or medically acceptable contraceptive methods (including intrauterine devices with established pregnancy failure rates, concurrent use of physical barrier contraceptive method and spermicide, vasectomy, tubotomy / tubal ligation, hysterectomy, etc.) from the examination until 30 days after the last dose of the investigational product. 7) Others a) Excessive use of alcohol in an amount of more than 30 g / day on average or positive in the alcohol test; b) Compulsive smoker with more than 10 cigarettes / day on average; and c) Caffeine intake in an amount exceeding 400 mg / day; and d) Any clinically relevant finding deemed inappropriate for participation in the clinical study at the investigator's discretion. 2. Clinical study method (1) Cohort 1A total of 24 subjects were divided into group 1 and group 2. During the first intervention period, the subjects in group 1 (12 people) were repeatedly administered 100 mg of tegoprazan twice daily for four days and once daily on the fifth day, on which a pharmacokinetic clinical study was conducted. During the second intervention period, after a 14-day washout period, they were repeatedly administered 1000 mg of amoxicillin and 500 mg of clarithromycin twice daily for four days and once daily on the fifth day. During the third intervention period, after a 14-day washout period, they were repeatedly administered 100 mg of tegoprazan, 1000 mg of amoxicillin, and 500 mg of clarithromycin twice daily for six days and once daily on the seventh day.After the last dose of each intervention period, pharmacokinetic blood samples were collected 17 times over 72 hours in the first period, 14 times over 48 hours in the second period, and 19 times over 120 hours in the third period. The drugs were administered to the subjects in group 2 (12 people) in the reverse order of the order in group 1 during the first and second intervention periods, and in the same order during the third intervention period. Pharmacokinetic blood samples were collected in the same manner as for group 1. (2) Cohort 2 As a result of screening (Day 28 - Day 2) prior to administering the first dose of the investigational product, a total of 36 subjects, who had met the selection and exclusion criteria (subjects T1-12, subjects T2-12 and R-12 subjects), were enrolled in a study to evaluate a change in intragastric pH and eradication rate following repeated co-administration of 50 mg / 100 mg of CJ12420 and amoxicillin / clarithromycin, and following repeated co-administration of 40 mg of pantoprazole and amoxicillin / clarithromycin. Group T1 received 50 mg of CJ-12420 and 1000 mg of amoxicillin / 500 mg of clarithromycin repeatedly twice daily for seven days; group T2 received 100 mg of CJ-12420 and 1000 mg of amoxicillin / 500 mg of clarithromycin repeatedly twice daily for seven days; and group R received 40 mg of pantoprazole and 1000 mg of amoxicillin / 500 mg of clarithromycin repeatedly twice daily for seven days. Intragastric pH was measured in all subjects on day 1 over a 24-hour period, and intragastric pH was also measured over 24 hours on day 1 and day 7 of repeated administration. In addition, a negative conversion rate was calculated on a follow-up visit by subjects who were identified as H. pylori positive on the UBT test during screening, and stability assessment was performed according to a predetermined schedule. η / ζζηη / ίζηζ / Β / γι 3. Evaluation element (1) Pharmacodynamic evaluation Evaluation variables Evaluation of average pH, percentage of time with pH> 6 and eradication success rate (2) Pharmacokinetic evaluation Evaluation parameters Mean plasma concentrations of tegoprazan, clarithromycin, and amoxicillin were measured, and patterns of plasma concentration over time and drug concentration over time were observed when tegoprazan was administered repeatedly alone, when amoxicillin / clarithromycin was administered repeatedly, and when tegoprazan, amoxicillin, and clarithromycin were administered repeatedly in combination. 4. Statistical analysis (1) Demographic information Descriptive statistics were presented with respect to key demographic variables (age, weight, height, etc.). (2) pharmacodynamic evaluation index Descriptive statistics were presented regarding intragastric pH for each administration group. In addition, an eradication success rate was calculated with respect to a negative conversion rate calculated as a result of UBT. (3) pharmacokinetic evaluation index The pharmacokinetics of tegoprazan, amoxicillin, and clarithromycin were evaluated. Descriptive statistics of the pharmacokinetic evaluation parameters are presented. Point estimates for the ratio of the geometric mean between each group and the 90% confidence interval were calculated from the primary pharmacokinetic evaluation parameters converted to logarithms using a linear mixed-effects model. 5. Results (1) Subject participation status and demographic distribution 1) Cohort 1 Of the 24 subjects enrolled in Cohort 1, 20 completed the entire clinical study; of the four dropouts, three withdrew their consent and one was dropped at the principal investigator's discretion. All subjects were male, and their average age, height, and weight were 27.3 ± 4.41 years, 172.92 ± 5.696 cm, and 70.04 ± 8.396 kg. 2) Cohort 2 Of the 221 volunteers who had received a screening test, 36 volunteers (T1: 12, T2: 12, and R: 12) were enrolled in the clinical study, of whom 34 subjects completed all stages of the clinical study, with the exception of two dropouts (T2: 1 and R: 1). The subjects were all male, with an average age, height, and weight of 25.6 ± 3.26 years, 175.98 ± 4.902 cm, and 74.28 ± 8.721 kg, respectively. (2) Pharmacodynamic evaluation On each of days 1 and 7, a mean pH value and a percentage of time that an intragastric pH is maintained at 6 or more were summarized in Figure 1 or Figure 2, respectively. Figure 1 shows a change in average mean pH over time and a percentage of time that intragastric pH is maintained at 6 or more on day 1, and Figure 2 shows a change in average mean pH over time and a percentage of time that intragastric pH is maintained at 6 or more on day 7. The mean baseline pH (Day 1) was 2.2 ± 1.03, 2.38 ± 1.17 and 1.87 ± 0.44 in the T1, T2 and R administration groups, respectively, and the mean Day 1 pH was 7.23 ± 0.47, 7.5 ± 0.31 and 5.11 ± 2.18, so a marked increase was observed compared to the baseline. either? zznn / Lznz / E / YiAi The mean average pH on day 7 was 6.94 ± 0.45, 7.33 ± 0.56 and 6.01 ± 1.44 in the T1, T2 and R administration groups, respectively, and therefore it was identified that the mean average pH on day 7 is similar to the mean average pH on day 1 in the T1 and T2 administration groups; and the mean average pH on day 7 increases more than that of day 1 in the R administration group, but is still lower compared to the T1 or T2 group. Furthermore, the percentage of time that intragastric pH remained at 6 or higher during the 24-hour baseline period (Day 1) was 10.19 ± 13.16% in the T1 administration group, 15.33 ± 10.61% in the T2 administration group, and 8.18 ± 6.96% in the R administration group, respectively. On Day 1, the percentage of time was 87.7 ± 10.71% in the T1 administration group, 96.26 ± 1.49% in the T2 administration group, and 49.71 ± 29.49% in the R administration group, indicating a significant increase compared to baseline. The percentage of time that intragastric pH was maintained at 6 or more on day 7 was 88.03 ± 8.73% in the T1 administration group, 96.33 ± 5.55% in the T2 administration group and 58.34 ± 29.21% in the R administration group, respectively, and therefore an increase was observed on day 7 compared to day 1, but without a noticeable difference between them, and a considerably low value was shown compared to the T1 or T2 administration group dosed with Tegoprazan. As identified above, the administration of Tegoprazan in the present invention greatly increased the average mean pH, as well as the time that the intragastric pH was maintained at 6 or higher for 24 hours. Furthermore, such administration greatly increased the pH to 6 or higher within a short period of two hours or less immediately after administration. On the other hand, one use case of pantoprazole was characterized by a slow rate of pH increase immediately after administration, and the mean pH and the time that the intragastric pH is maintained at 6 or more for 24 hours are also less compared to the present invention. In other words, it was demonstrated that the use of Tegoprazan of the present invention maintains a pH close to the pKa value of antibiotics, i.e., amoxicillin and clarithromycin, to improve the stability of the antibiotics and greatly reduce the minimum inhibitory concentration of the antibiotics. It also has a long half-life to maintain an elevated intragastric pH for a certain period of time or longer, so that the use of Tegoprazan can maximize the eradication effect of amoxicillin and clarithromycin. (3) Evaluation of pharmacokinetic parameters. The pharmacokinetic characteristics of tegoprazan were evaluated after repeated administration of 100 mg of tegoprazan twice daily alone, repeated administration of 1000 mg of amoxicillin and 500 mg of clarithromycin twice daily in combination, or repeated administration of 100 mg of tegoprazan, 1000 mg of amoxicillin, and 500 mg of clarithromycin twice daily in combination. As a result, the Cmax of tegoprazan increased by 2.24-fold and the AUC increased by 2.70-fold when administered in combination with amoxicillin / clarithromycin; the Cmax and AUC of clarithromycin showed a trend toward increasing when administered in combination with tegoprazan. Therefore, it was confirmed that administering these three formulations in combination increases the bioavailability of tegoprazan and clarithromycin. Example 4: Clinical Study 2 1. Selection of subjects To identify a Helicobacter pylori eradication effect of the present invention, a clinical study was designed according to a randomized, open-label, active-controlled, parallel, multiple-dose design. A total of 350 patients were evaluated, and all 350 patients were enrolled in the clinical trial. Inclusion criteria Unless otherwise specified, study participants were required to meet all inclusion criteria listed below. (1) Healthy adults aged between 20 and 75 years at the time of screening (2) Those who complain of having epigastric discomfort or? zznn / Lznz / E / YiAi (3) H. pylori positive as a result of the detection (4) Those who correspond to any of the following cases in upper gastrointestinal endoscopy as a result of screening: - Peptic ulcer (gastric ulcer or duodenal ulcer) - Diagnosis of gastric ulcer or healed duodenal ulcer - History of gastric or duodenal ulcer in medical record, although there is no scar - Chronic atrophic gastritis (5) Those who can understand and comply with the instructions and participate in the entire study (6) Those who voluntarily decide to participate in the study and sign a written consent form (7) Those who agree to the use of medically valid contraceptive measures (including medically infertile status) during the study - Female volunteers who are medically infertile can participate in the study: Those who have gone through menopause (amenorrhea for 24 months or more), hysterectomy, salpingectomy or bilateral oophorectomy. - Medically valid contraceptive measures: intrauterine device (loop, Mirena), physical contraception (male condom, female condom (Femidom)), subdermal contraceptive implant (Implanon), long-acting contraceptive injections or tubotomy and tubal ligation and vasectomy (however, oral contraceptives are not allowed during the study and dual contraception is recommended during the study to prevent pregnancy) Exclusion criteria Participants were excluded from the study if they met any of the following criteria. (1) Cannot undergo upper gastrointestinal endoscopy (2) Those who received H. pylori eradication therapy (3) Those who have acute upper gastrointestinal bleeding, acute gastric mucosal injury (AGML) or acute duodenal mucosal injury (ADML) on upper gastrointestinal endoscopy (4) Those who have undergone or will undergo surgery that could affect gastric acid secretion (e.g., upper gastrointestinal resection or vagotomy) - However, simple perforation surgery, appendectomy, cholecystectomy, and endoscopic removal of benign tumors are excluded. (5) History of Zollinger-Ellison syndrome or gastric acid hypersecretion disorders (6) Those diagnosed with gastric outlet obstruction (GOO) or diagnosed with gastric cancer on upper gastrointestinal endoscopy during screening (7) Those who received full-dose proton pump inhibitors (PPIs) or histamine H2 receptor antagonists within 14 days prior to screening (8) Those who received antibiotics for H. pylori eradication or drugs containing bismuth formulations within 28 days prior to screening (9) Pregnant or breastfeeding woman (10) Clinically significant abnormal screening results - AST, ALT, ALP, γ-GT or total bilirubin values ​​are two or more times higher than the upper normal limit (UNL) of each testing institution - BUN or creatinine values ​​are 1.5 or more times higher than the upper normal limit (UNL) of each testing institution (11) clinically significant abnormal electrocardiogram - Major arrhythmia, multifocal PVC or 2° AV block abnormality (12) History of malignant tumors in five years. - However, if a participant achieved complete remission (CR, pCR) of tumors and had no recurrence for more than five years, or if a participant, after complete removal of tumors by endoscopic resection, had no recurrence for more than three years, they are allowed to be included. (13) Clinically significant abnormalities in the liver, kidney, system ΖΖΠΠ / ίΖΠΖ / Ε / ΥΙΛΙ cardiovascular, respiratory system, endocrine system or central nervous system. (14) History of hypersensitivity reactions to the main ingredient or bulking agent of tegoprazan or proton pump inhibitors (PPIs), penicillin antibiotics and macrolide antibiotics. (15) Those who have scheduled surgery requiring hospital care or require surgical treatment during the study. (16) Those who participated in other clinical studies (except clinical study CJ_APA_303) within four weeks of the second visit (date of randomized clinical study) Those who participated or are participating in a non-interventional study (observational study or survey) that would not affect the outcome and safety assessment of the current study, as determined by the investigator, may participate in the study. In addition, those who signed a written consent form to participate in another clinical study but were subsequently dropped after screening without receiving any investigational products or care may participate in the study. - However, if a participant participated in study [CJ_APA_303] and it was confirmed that the ulcer had healed, they are allowed to participate in the study. (17) In addition to the above criteria, those who are not eligible for the study according to the clinically significant opinion of the investigator based on medical determination 2. Clinical study method A total of 350 subjects (TAC-175, LAC-175) who met all inclusion criteria and non-exclusion criteria as a result of screening (endoscopy) at the first visit prior to administration of the first dose of investigational products (D-14 - D-0) were enrolled in the study to evaluate H. pylori eradication rates when tegoprazan 50 mg and amoxicillin / clarithromycin are repeatedly administered in combination and lansoprazole 30 mg and amoxicillin / clarithromycin are repeatedly administered in combination. The TAC group was repeatedly administered tegoprazan 50 mg, amoxicillin qj zznn / Lznz / E / YiAi 1000 mg / clarithromycin 500 mg twice a day for seven days, and the LAC group was repeatedly administered with lansoprazole 30 mg, amoxicillin 1000 mg / clarithromycin 500 mg twice a day for seven days. After completing the eligibility assessment through screening, participants were advised to begin taking the prescribed investigational products at the second visit (day 0) the following morning (day 1). A medication administration log was maintained for the study participant from the first day of investigational product administration. Participants were advised to arrive on an empty stomach without taking any research products on the Third Visit (Day 8). 3. Evaluation element (1) H. pylori eradication rate according to clarithromycin MIC The MIC criteria for clarithromycin are described below. < 0.5 ( Mg / % ): Susceptible and Intermediate > 1 ( Mg / ): Resistant (2) H. pylori eradication rate according to lesions in upper digestive endoscopy. 4. Results Based on H. pylori eradication rates according to clarithromycin MIC, the TAC group, in which tegoprazan 50 mg and amoxicillin / clarithromycin were administered repeatedly in combination, was found to have an H. pylori eradication success rate of 92% and was more effective at eradicating H. pylori than the LAC group, in which lansoprazole 30 mg and amoxicillin / clarithromycin were administered repeatedly in combination. The H. pylori eradication effect was also observed in patients with bacterial resistance when tegoprazan 50 mg and amoxicillin / clarithromycin were administered repeatedly in combination. Furthermore, based on H. pylori eradication rates according to lesions on upper gastrointestinal endoscopy, the TAC group had an H. pylori eradication rate of 76.19% in peptic ulcer disease (PUD) and was more effective at eradicating H. pylori than the LAC group. The TAC group also had an H. pylori eradication rate of 68.15% in chronic atrophic gastritis (CAG) and had an eradication effect equivalent to or stronger than that of the LAC group. The above results demonstrate that the pharmaceutical composition according to the present invention could have an excellent Helicobacter pylori eradication effect by maximizing the eradication effects of amoxicillin and clarithromycin. Industrial applicability A pharmaceutical composition of the present invention maintains an intragastric pH at a certain level or higher for a certain period of time or longer, thereby maintaining a pH close to the pKa value of amoxicillin and clarithromycin to improve the stability of the antibiotics and thus greatly reduce the minimum inhibitory concentration of the antibiotics to maximize the eradication effect of amoxicillin and clarithromycin. Furthermore, this composition exhibits an excellent effect on the eradication of even antibiotic-resistant Helicobacter pylori and can therefore also be used effectively to eradicate resistant strains. This composition continues to maintain the pH at a certain level or higher for an extended period and thus has the advantage of achieving remarkably high medication compliance.Furthermore, this composition has an advantage, as it can be available before or after meals without requiring dietary therapy, unlike existing combination therapies, and is therefore expected to be of valuable use in a related field of the pharmaceutical industry.

Claims

1. A pharmaceutical composition for eradicating Helicobacter pylori, comprising: a compound represented by the following formula 1, its optical isomers or its pharmaceutically acceptable salts; amoxicillin or its pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts as the active ingredient: Formula 1 2. The pharmaceutical composition according to claim 1, wherein the compound represented by formula 1 is a compound represented by the following formula 2: Formula 2 3. The pharmaceutical composition according to claim 1, wherein said composition comprises 10 mg to 500 mg of the compound represented by formula 1 or pharmaceutically acceptable salts thereof, 100 mg to 4 g of amoxicillin or pharmaceutically acceptable salts thereof, and 50 mg to 3 g of clarithromycin or pharmaceutically acceptable salts thereof.

4. The pharmaceutical composition according to claim 1, wherein a percentage of time in which an intragastric pH is maintained at 5.0 or more for a period of up to 24 hours after administration thereof is at least 60% in the case of said pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition increases an intragastric pH to 5 or more within three hours after administration thereof.

6. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition eradicates antibiotic-resistant Helicobacter pylori.

7. The pharmaceutical composition according to claim 6, wherein said antibiotic-resistant Helicobacter pylori is resistant to amoxicillin or clarithromycin.

8. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is administered to subjects infected with Helicobacter pylori.

9. The pharmaceutical composition according to claim 8, wherein said Helicobacter pylori is antibiotic-resistant Helicobacter pylori.

10. The pharmaceutical composition according to claim 9, wherein said antibiotic-resistant Helicobacter pylori is resistant to amoxicillin or clarithromycin.

11. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is of an oral administration type.

12. A combination comprising: a compound represented by the following formula 1, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or pharmaceutically acceptable salts thereof; and clarithromycin or pharmaceutically acceptable salts thereof: o? zznn / Lznz / E / YiAi Formula 1 13. The combination according to claim 12, wherein said combination is for eradicating Helicobacterpylori.

14. A kit comprising a combination for eradicating Helicobacter pylori, comprising: a compound represented by the following formula 1, its optical isomers or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts thereof; and clarithromycin or its pharmaceutically acceptable salts thereof: Formula 1 15. A method for eradicating Helicobacter pylori, comprising a step of administering a pharmaceutical composition, comprising: a compound 5 represented by the following formula 1, its optical isomers or pharmaceutically acceptable salts thereof; amoxicillin or its pharmaceutically acceptable salts thereof; and clarithromycin or its pharmaceutically acceptable salts thereof as an active ingredient, in subjects who require it: 10 Formula 1 16. A use of a compound represented by the following formula 1, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its 15 pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts, in the preparation of a drug for eradicating Helicobacter pylori: Formula 1 17. A use of a compound represented by the following formula 1, optical isomers thereof or pharmaceutically acceptable salts thereof; amoxicillin or its 5 pharmaceutically acceptable salts; and clarithromycin or its pharmaceutically acceptable salts for the eradication of Helicobacter pylori: