Pharmaceutical composition comprising benzimidazole derivative compound

Abstract

To provide a compound and a pharmaceutical composition for preventing the recurrence of gastroesophageal reflux disease.SOLUTION: The present invention provides a pharmaceutical composition that includes tegoprazan, a compound represented by the following formula, or a pharmaceutically acceptable salt thereof in amount of 25 mg as tegoprazan, with no adverse reactions observed in gastrin safety evaluations.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the maintenance treatment of gastroesophageal reflux disease with pharmaceutical compositions containing benzimidazole derivative compounds. [Background technology]

[0002] With the recent Westernization of dietary habits, gastroesophageal reflux disease (GERD) is on the rise in Korea. Gastroesophageal reflux disease (GERD) is defined as the backflow of stomach acid into the esophagus, causing symptoms and damage to the lining of the esophagus, including heartburn and acid reflux, which can become serious health problems and reduce quality of life.

[0003] Among the causative factors of gastroesophageal reflux disease, transient relaxation of the lower esophageal sphincter is an important factor. Therefore, methods to inhibit this transient relaxation of the lower esophageal sphincter could theoretically be considered for treating gastroesophageal reflux disease. However, such methods have not yet achieved significant clinical benefits and are still in the research stage. To date, the most commonly used treatment for gastroesophageal reflux disease has been the inhibition of gastric acid secretion using proton pump inhibitors or H2 receptor blockers.

[0004] However, in patients with GERD, approximately 60-70% of patients will develop GERD again within a certain period of time, even after their symptoms have been treated with gastric acid inhibitors. This recurrence rate is the same for both erosive and non-erosive GERD.

[0005] Thus, when gastroesophageal reflux disease recurs, even if the same dose of gastric acid inhibitor used to be effective in the previous treatment is administered, this administration may not be fully effective, or the symptoms may become worse than before. Furthermore, in some cases, other complications may occur due to gastroesophageal reflux disease.

[0006] Therefore, after gastroesophageal reflux disease has been treated, it may also be very important to safely and effectively prevent the recurrence of gastroesophageal reflux disease without side effects. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Korean Patent Registration No. 10-1088247

[0008] Technical issues

[0009] The present invention provides a pharmaceutical composition for preventing the recurrence of gastroesophageal reflux disease, comprising tegoprazan, a compound represented by the following chemical formula 1, or 25 mg of a pharmaceutically acceptable salt thereof as tegoprazan: [Chemical formula 1] JPEG2025122089000001.jpg69159 Technical solution

[0010] The present invention provides a pharmaceutical composition for preventing the recurrence of gastroesophageal reflux disease, comprising tegoprazan, a compound represented by the following chemical formula 1, or 25 mg of a pharmaceutically acceptable salt thereof as tegoprazan: [Chemical formula 1] JPEG2025122089000002.jpg69159

[0011] A pharmaceutical composition containing tegoprazan or a pharmaceutically acceptable salt thereof as tegoprazan in an amount of 25 mg can effectively prevent the recurrence of gastroesophageal reflux disease.

[0012] The pharmaceutical composition of the present invention, which contains 25 mg of tegoprazan or a pharmaceutically acceptable salt thereof, can repeatedly prevent the recurrence of gastroesophageal reflux disease. Furthermore, the pharmaceutical composition of the present invention has excellent stability and can sufficiently prevent the recurrence of gastroesophageal reflux disease without side effects, even when taken over a long period of time.

[0013] The pharmaceutical composition of the present invention containing 25 mg of tegoprazan or a pharmaceutically acceptable salt thereof is not affected by Helicobacter pylori infection or CYP gene polymorphisms, and can effectively and sufficiently prevent the recurrence of gastroesophageal reflux disease without side effects.

[0014] In the present invention, tegoprazan, a compound represented by Chemical Formula 1, is also called "(S)-4-(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide."

[0015] In the present invention, gastroesophageal reflux disease is a disease in which stomach acid or stomach contents rise into the esophagus, causing burning pain or pain in the chest, and may be non-erosive gastroesophageal reflux disease or erosive gastroesophageal reflux disease.

[0016] In the present invention, the term "subject" may refer to a mammal, including a human, and in particular to a human.

[0017] In the present invention, a pharmaceutical composition containing 25 mg of tegoprazan can mean that the pharmaceutical composition contains tegoprazan or a pharmaceutically acceptable salt thereof in an amount equivalent to 25 mg of tegoprazan.

[0018] In the present invention, the occurrence or treatment of gastroesophageal reflux disease can be determined by endoscopic examination or by determining whether symptoms of gastroesophageal reflux disease are present. In particular, erosive gastroesophageal reflux disease is determined by the presence of erosions and the presence of symptoms of heartburn and / or gastric acid reflux. More specifically, the occurrence and severity of erosive gastroesophageal reflux disease can be determined by whether it corresponds to LA grades A to D by endoscopic examination.

[0019] In the present invention, preventing the recurrence of gastroesophageal reflux disease can include preventing the recurrence of gastroesophageal reflux disease, or inhibiting or delaying the recurrence of gastroesophageal reflux disease.

[0020] The present invention provides a pharmaceutical composition containing 25 mg of tegoprazan for preventing recurrence of gastroesophageal reflux disease by administering the composition to a subject who has been diagnosed with gastroesophageal reflux disease and subsequently treated for the disease.

[0021] In an embodiment of the present invention, the subject to whom the pharmaceutical composition containing 25 mg of tegoprazan is administered may be a person who has been identified as having been treated after the onset of gastroesophageal reflux disease.

[0022] In the present invention, the subject may be a person who has been diagnosed with gastroesophageal reflux disease or who has experienced symptoms of gastroesophageal reflux disease before administration of a pharmaceutical composition containing 25 mg of tegoprazan, and in particular, a person who has been diagnosed with non-erosive gastroesophageal reflux disease or erosive gastroesophageal reflux disease or who has experienced symptoms such as heartburn / acid reflux.

[0023] In an embodiment of the present invention, the subject may be a person in whom no erosions are observed when an upper gastrointestinal endoscopy is performed before administration of a pharmaceutical composition containing 25 mg of tegoprazan, but who has been diagnosed with non-erosive gastroesophageal reflux disease before administration of a pharmaceutical composition containing 25 mg of tegoprazan, and in particular, who is experiencing symptoms such as heartburn / acid reflux.

[0024] In an embodiment of the present invention, the subject may be a person who has been diagnosed with erosive gastroesophageal reflux disease before administration of a pharmaceutical composition containing 25 mg of tegoprazan, and in particular, a person who has been diagnosed with erosive gastroesophageal reflux disease corresponding to LA grades A to D by performing upper gastrointestinal endoscopy before administration of a pharmaceutical composition containing 25 mg of tegoprazan.

[0025] In an embodiment of the present invention, the subject may have experienced gastroesophageal reflux disease one or more times. For example, the subject may have experienced a recurrence of gastroesophageal reflux disease.

[0026] In the present invention, a state in which a subject's gastroesophageal reflux disease has been treated may refer to a state in which the subject is free of gastroesophageal reflux disease symptoms. In particular, a state in which a subject's gastroesophageal reflux disease has been treated may refer to a state in which the subject no longer experiences symptoms of gastroesophageal reflux disease, such as heartburn and / or acid reflux.

[0027] In an embodiment of the present invention, the state of a subject's gastroesophageal reflux disease being treated can be identified by the presence of erosion during gastroscopy. In particular, the state of a subject's gastroesophageal reflux disease being treated can mean a state in which no erosion is observed when upper gastrointestinal endoscopy is performed on the subject. More specifically, the state of a subject's gastroesophageal reflux disease being treated can mean a state in which no erosion is observed when upper gastrointestinal endoscopy is performed on the subject, corresponding to any of LA grades A to D.

[0028] In the present invention, the recurrence of gastroesophageal reflux disease may refer to a state in which a subject diagnosed with gastroesophageal reflux disease is treated with drug therapy or the like, and then the subject is re-diagnosed with the onset of gastroesophageal reflux disease, or the symptoms of gastroesophageal reflux disease, such as heartburn or gastric acid reflux, reoccur.

[0029] In the present invention, the recurrence of gastroesophageal reflux disease may refer to a state in which erosions are found in a subject diagnosed with gastroesophageal reflux disease and treated with drug therapy or the like, and then the subject is subjected to upper gastrointestinal endoscopy. In particular, the recurrence of gastroesophageal reflux disease may be a state corresponding to erosive gastroesophageal reflux disease of grades A to D based on the LA grade, as determined by upper gastrointestinal endoscopy.

[0030] In the present invention, prevention of recurrence may mean preventing, delaying, or inhibiting a subject diagnosed with gastroesophageal reflux disease from being diagnosed with gastroesophageal reflux disease again or from experiencing the symptoms of gastroesophageal reflux disease again after the subject has been treated with drug therapy or the like.

[0031] In an embodiment of the present invention, prevention of recurrence of gastroesophageal reflux disease may mean maintaining a state in which symptoms of gastroesophageal reflux disease, such as heartburn and acid reflux, do not recur for a certain period of time after gastroesophageal reflux disease has been treated.

[0032] In an embodiment of the present invention, prevention of recurrence of gastroesophageal reflux disease means maintaining a state in which no erosion is observed by endoscopic examination for a certain period of time after gastroesophageal reflux disease has been treated, and in particular may mean maintaining a state in which no erosive gastroesophageal reflux disease of grades A to D based on the LA grade is observed by upper gastrointestinal endoscopy for a certain period of time.

[0033] The composition of the present invention can effectively prevent and / or inhibit the recurrence of gastroesophageal reflux disease even in subjects diagnosed with moderate to severe gastroesophageal reflux disease. In particular, the composition of the present invention can effectively prevent and / or inhibit the recurrence of gastroesophageal reflux disease even in subjects who have shown moderate to severe symptoms of gastroesophageal reflux disease and / or who have experienced erosive gastroesophageal reflux disease corresponding to LA grade C or D.

[0034] The compositions of the present invention can be administered to subjects who have been diagnosed with gastroesophageal reflux disease one or more times. In particular, the subjects can be those who have been diagnosed with gastroesophageal reflux disease one or more times, two or more times, or three or more times. Here, a subject who has been diagnosed with gastroesophageal reflux disease two or more times can be those who have been diagnosed with non-erosive gastroesophageal reflux disease only, erosive gastroesophageal reflux disease only, or both non-erosive and erosive gastroesophageal reflux disease. For example, the pharmaceutical compositions of the present invention can effectively prevent and / or inhibit the recurrence of non-erosive gastroesophageal reflux disease and / or erosive gastroesophageal reflux disease even in subjects who have been diagnosed with non-erosive gastroesophageal reflux disease and / or erosive gastroesophageal reflux disease one or more times, two or more times, or three or more times.

[0035] In an embodiment of the present invention, the subject to whom the pharmaceutical composition containing 25 mg of tegoprazan is administered may be a person identified as having been treated after the onset of gastroesophageal reflux disease, wherein the subject may have been diagnosed with gastroesophageal reflux disease within about 12 weeks prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan.

[0036] In an embodiment of the present invention, the subject to whom the pharmaceutical composition containing 25 mg of tegoprazan is administered may be a person identified as having been treated after the onset of gastroesophageal reflux disease, wherein the subject may have experienced symptoms of gastroesophageal reflux, such as heartburn or acid reflux, within about 12 weeks prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan.

[0037] In an embodiment of the present invention, the subject to be administered a pharmaceutical composition containing 25 mg of tegoprazan may be a person identified as having non-erosive gastroesophageal reflux disease (GERD) that has been treated after the onset of the disease, in which no erosions are observed by upper gastrointestinal endoscopy performed within about 12 weeks prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan, but who has experienced symptoms of GERD, such as heartburn or acid reflux.

[0038] In an embodiment of the present invention, the subject to be administered a pharmaceutical composition containing 25 mg of tegoprazan may be a person identified as having been treated after the onset of erosive gastroesophageal reflux disease. Here, the subject may be a person diagnosed with erosive gastroesophageal reflux disease within about 12 weeks prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan. In particular, the subject may be a person diagnosed with erosive gastroesophageal reflux disease corresponding to LA grades A to D by upper gastrointestinal endoscopy within about 12 weeks prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan.

[0039] In an embodiment of the present invention, the subject to whom the pharmaceutical composition containing 25 mg of tegoprazan is administered may be a person identified as having been treated after the onset of gastroesophageal reflux disease, wherein the subject may be a person identified as having been treated for gastroesophageal reflux disease within about 14 days, particularly within 7 days, prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan.

[0040] In an embodiment of the present invention, the subject to whom the pharmaceutical composition containing 25 mg of tegoprazan is administered may be a person identified as having been treated after the onset of gastroesophageal reflux disease, and the subject may be a person who has not experienced symptoms of heartburn or acid reflux due to gastroesophageal reflux disease within about 14 days, particularly within 7 days, prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan.

[0041] In an embodiment of the present invention, the subject to whom a pharmaceutical composition containing 25 mg of tegoprazan is administered may be a person identified as having been treated after the onset of non-erosive gastroesophageal reflux disease, in which the subject may not have experienced symptoms of heartburn or acid reflux due to gastroesophageal reflux disease within about 14 days, particularly within 7 days, prior to administration of the pharmaceutical composition containing 25 mg of tegoprazan.

[0042] In an embodiment of the present invention, the subject to whom a pharmaceutical composition containing 25 mg of tegoprazan is administered may be a subject identified as having been treated after the onset of erosive gastroesophageal reflux disease. Here, the subject may be a subject identified as having been treated for erosive gastroesophageal reflux disease within about 14 days, particularly within 7 days, prior to administration of a pharmaceutical composition containing 25 mg of tegoprazan. In particular, the subject may not have been identified as having erosive gastroesophageal reflux disease corresponding to LA grades A to D by upper gastrointestinal endoscopy within about 14 days, particularly within 7 days, prior to administration of a pharmaceutical composition containing 25 mg of tegoprazan.

[0043] In an embodiment of the present invention, a subject administered a pharmaceutical composition containing 25 mg of tegoprazan may remain free from the onset of gastroesophageal reflux disease or its symptoms, such as heartburn or acid reflux, for 52 weeks or more, 24 weeks or more, particularly 4, 12, 24, 52 weeks or more after administration of the pharmaceutical composition.

[0044] In an embodiment of the present invention, a subject to whom a pharmaceutical composition containing 25 mg of tegoprazan is administered can maintain a state in which erosive gastroesophageal reflux disease does not recur for 52 weeks or more, 24 weeks or more, particularly 4, 12, 24, and 52 weeks or more. In particular, a subject to whom a pharmaceutical composition containing 25 mg of tegoprazan is administered can be one in which erosive gastroesophageal reflux disease corresponding to LA grades A to D has not been identified by upper gastrointestinal endoscopy for 12 to 24 weeks or more, particularly 12, 24, and 52 weeks or more since the administration of the pharmaceutical composition.

[0045] The present invention provides a pharmaceutical composition containing 25 mg of tegoprazan for preventing the recurrence of erosive gastroesophageal reflux disease by administering it to a subject who has been diagnosed with erosive gastroesophageal reflux disease and then treated for the disease.The present invention provides a pharmaceutical composition containing 25 mg of tegoprazan for preventing the recurrence of erosive gastroesophageal reflux disease by administering it to a subject who has been diagnosed with erosive gastroesophageal reflux disease and then treated for the disease.

[0046] In an embodiment of the present invention, the subject may have been treated for gastroesophageal reflux disease by administering a drug such as a gastric acid secretion inhibitor prior to administration of a pharmaceutical composition containing 25 mg of tegoprazan.

[0047] In an embodiment of the present invention, the subject may be a person who, prior to administration of a pharmaceutical composition containing 25 mg of tegoprazan, has been identified as having been cured of erosive gastroesophageal reflux disease by administering a drug after a diagnosis of erosive gastroesophageal reflux disease.

[0048] In an embodiment of the present invention, the subject may be a person who, prior to administration of a pharmaceutical composition containing 25 mg of tegoprazan, has been identified as having been cured of non-erosive gastroesophageal reflux disease by administering a drug after a diagnosis of non-erosive gastroesophageal reflux disease.

[0049] In an embodiment of the present invention, the gastric acid secretion inhibitor may be at least one of a proton pump inhibitor (PPI), an antigastrin agent, an anticholinergic agent, and an H2 blocker; particularly at least one of cimetidine, ranitidine, famotidine, nizatidine, omeprazole, lansoprazole, esomeprazole, rabeprazole, and pantoprazole; more particularly a proton pump inhibitor; even more particularly at least one of omeprazole, lansoprazole, esomeprazole, rabeprazole, and pantoprazole.

[0050] In an embodiment of the present invention, the subject to whom a pharmaceutical composition containing 25 mg of tegoprazan is administered may be infected with H. pylori.

[0051] In an embodiment of the present invention, a pharmaceutical composition containing 25 mg of tegoprazan can effectively prevent the recurrence of gastroesophageal reflux disease without significantly affecting the presence of H. pylori infection in the subject to which it is administered.

[0052] In an embodiment of the present invention, a subject to be administered a pharmaceutical composition containing 25 mg of tegoprazan may have a polymorphism in a CYP gene. In particular, a subject to be administered a pharmaceutical composition containing 25 mg of tegoprazan may have at least one polymorphism in a gene selected from the group consisting of CYP1A2, CYP12C9, CYP12C19, CYP12D6, CYP12E1, and CYP13A4. More specifically, a subject to be administered a pharmaceutical composition containing 25 mg of tegoprazan may have a polymorphism in the CYP2C19 gene and / or the CYP3A4 gene.

[0053] In an embodiment of the present invention, a pharmaceutical composition containing 25 mg of tegoprazan can effectively prevent the recurrence of gastroesophageal reflux disease without significantly affecting the polymorphisms of CYP genes in a subject to which it is administered. In particular, a pharmaceutical composition containing 25 mg of tegoprazan can effectively prevent the recurrence of gastroesophageal reflux disease without significantly affecting the polymorphisms of at least one gene selected from the group consisting of CYP1A2, CYP12C9, CYP12C19, CYP12D6, CYP12E1, and CYP13A4 in a subject to which it is administered. More specifically, a pharmaceutical composition containing 25 mg of tegoprazan can effectively prevent the recurrence of gastroesophageal reflux disease without significantly affecting the polymorphisms of the CYP2C19 gene and / or CYP3A4 gene in a subject to which it is administered.

[0054] In an embodiment of the present invention, a pharmaceutical composition containing 25 mg of tegoprazan may be administered once to three times a day for 52 weeks or more, particularly once to three times a day for 4 to 52 weeks, more particularly once a day for 4 to 12 weeks or 4 to 24 weeks, or 4 to 52 weeks.

[0055] In an embodiment of the present invention, a pharmaceutical composition containing 25 mg of tegoprazan can be formulated into a unit dosage form such as a tablet or capsule. When the pharmaceutical composition containing 25 mg of tegoprazan is formulated into a unit dosage form, the unit dosage form can be administered once to three times a day, particularly once a day regardless of meals, and can effectively prevent recurrence of gastroesophageal reflux disease regardless of when it is administered each day.

[0056] In the embodiment of the present invention, pharmaceutically acceptable salt refers to the salt formed with any inorganic acid, organic acid or base, which does not cause serious irritation to the subject to be administered and does not impair the biological activity and physical properties of the compound.As the salt, the salt commonly used in the art, such as the acid addition salt formed with pharmaceutically acceptable free acid, can be used.Pharmaceutically acceptable salts include, in particular, hydrazine salt, acetate salt, adipate salt, aspartate salt, benzoate salt, besylate salt, bicarbonate / carbonate salt, bisulfate / sulfate salt, borate salt, camsylate salt, citrate salt, cyclamate salt, edisylate salt, esylate salt, formate salt, fumarate salt, glucept salt, gluconate salt, glucuronate salt, hexafluorophosphate salt, hybenzate salt, hydrochloride / chloride salt, hydrobromide / bromide salt, hydroiodide / iodide salt, isethionate salt. The salt may be selected from the group consisting of, but not limited to, salts of tegoprazan, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Any salt may be used without limitation as long as it can normally exhibit the pharmacological activity of tegoprazan.

[0057] The pharmaceutical composition of the present invention for preventing the recurrence of gastroesophageal reflux disease, which contains tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan, may further contain a pharmaceutically acceptable additive, a conventionally used suitable carrier, excipient, disintegrant, binder, glidant or diluent.

[0058] As used herein, the term "pharmaceutically acceptable additives" may include carriers, excipients, disintegrants, binders, glidants, or diluents that do not stimulate living organisms and do not impair the biological activity and properties of the administered compound. The types of additives that can be used in the present invention are not particularly limited, and any additives can be used as long as they are conventionally used and pharmaceutically acceptable in the art. Non-limiting examples of additives include mannitol, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or mixtures thereof. Furthermore, other conventional additives, such as antioxidants, buffers, and / or bacteriostatic agents, can be added and used as needed.

[0059] The pharmaceutical composition of the present invention for preventing the recurrence of gastroesophageal reflux disease, which contains tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan, can be formulated for oral administration, and in particular can be formulated as a tablet, capsule, etc.

[0060] The present invention provides a method for preventing the recurrence of gastroesophageal reflux disease by administering to a subject a pharmaceutical composition containing tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg calculated as tegoprazan.

[0061] The present invention provides a method for preventing the recurrence of gastroesophageal reflux disease by administering a pharmaceutical composition containing tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan to a subject who has been diagnosed with and subsequently treated for gastroesophageal reflux disease.

[0062] The present invention provides a method for preventing the recurrence of erosive gastroesophageal reflux disease by administering a pharmaceutical composition containing tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan to a subject who has been diagnosed with erosive gastroesophageal reflux disease and then treated for the erosive gastroesophageal reflux disease.

[0063] The present invention provides use of a pharmaceutical composition containing tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan, for preventing the recurrence of gastroesophageal reflux disease by administering the pharmaceutical composition to a subject.

[0064] The present invention provides use of a pharmaceutical composition comprising tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan, for preventing recurrence of gastroesophageal reflux disease by administering the pharmaceutical composition to a subject who has been diagnosed with gastroesophageal reflux disease and subsequently treated for the disease.

[0065] The present invention provides use of a pharmaceutical composition comprising tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan, for preventing the recurrence of erosive gastroesophageal reflux disease by administering the pharmaceutical composition to a subject who has been diagnosed with erosive gastroesophageal reflux disease and subsequently treated for erosive gastroesophageal reflux disease.

[0066] The descriptions of the pharmaceutical compositions of the present invention equally apply to the methods of treatment and uses, unless they are mutually inconsistent.

[0067] The present invention enables effective long-term prevention of recurrence of gastroesophageal reflux disease without side effects by administering to a subject a pharmaceutical composition containing tegoprazan or a pharmaceutically acceptable salt thereof in an amount of 25 mg as tegoprazan. [Brief explanation of the drawings]

[0068] [Figure 1] FIG. 1 shows a schematic diagram of the process of a clinical trial conducted using the pharmaceutical composition of the present invention. Aspects of the invention

[0069] The present invention will be described in more detail through the following embodiments. These embodiments are provided only for the purpose of describing the present invention in more detail, and therefore, the scope of the present invention is not limited thereto.

[0070] Preparation Example 1: Preparation of formulation (1) - Tegoprazan 25 mg tablets

[0071] A formulation containing 25 mg of 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide (tegoprazan) as the active ingredient was prepared. The active ingredient was mixed with mannitol, microcrystalline cellulose, and croscarmellose sodium. The filler was contained in the formulation in a ratio of 1 to 99% by weight (25 mg of mannitol and 40 mg of microcrystalline cellulose) based on the weight of the final formulation. The disintegrant was used in a ratio of 1 to 20% by weight (5 mg of croscarmellose sodium) based on the weight of the final formulation.

[0072] A binder solution containing hydroxypropyl cellulose and purified water was added and the mixture was granulated, and the binder content was used in the range of 4 to 40 wt% (hydroxypropyl cellulose 4 mg) relative to the weight part of the active ingredient.

[0073] After the drying process, the granules were sized and the resulting granules, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate were added to the granules and mixed together.

[0074] The diluent ratio was 1-10% by weight (1 mg of colloidal silicon dioxide) relative to the weight of the final formulation, and the lubricant ratio was 1-10% by weight (1 mg of magnesium stearate) relative to the weight of the final formulation. The resulting mixture was then compressed to prepare tablets.

[0075] The tablets were coated with a film coating agent, which was prepared to have a weight ratio of 2 to 6% (3 mg) of the weight of the final formulation.

[0076] Preparation Example 2: Placebo for tegoprazan 25 mg

[0077] A placebo for tegoprazan 25 mg was prepared in the same manner as in Preparation Example 1, except that the main ingredient, tegoprazan, was not used.

[0078] Preparation Example 3: Preparation of lansoprazole 15 mg formulation

[0079] For the lansoprazole preparation, Lanston Capsules 15 mg (lansoprazole 15 mg, Daiichi Pharmaceutical Co., Ltd.) were purchased and used.

[0080] Preparation Example 4: Placebo for lansoprazole 15 mg

[0081] The placebo for lansoprazole 15 mg was prepared in the same manner as that for preparing Lanston capsules by adding pharmaceutically acceptable excipients, except that the main ingredient, lansoprazole, was not used.

[0082] Preparation Example 5:

[0083] For esomeprazole preparations, Nexium tablets 20 mg (esomeprazole 20 mg, AstraZeneca Korea Co., Ltd.) were purchased and used.

[0084] Example 1 1. Dosage, administration period, and subject selection Tegoprazan and esomeprazole were administered orally for 7 days (open-label, active-controlled, parallel-group, and repeated-dose study) as shown in Table 1. [Table 1]

[0085] Selection Criteria Unless otherwise specified, clinical trial subjects must meet all of the following inclusion criteria to participate in this clinical trial.

[0086] (1) Healthy male volunteers aged 19–50 years (inclusive); (2) Body mass index (BMI) of 18 kg / m at the time of screening 2 ~27 kg / m 2 (inclusive) and weighed between 55 kg and 90 kg (inclusive); (3) those who were negative for Helicobacter pylori; (4) agree to use effective contraception and not donate sperm from the first dose of the investigational drug until 30 days after the last dose of the investigational drug; and (5) Those who are deemed appropriate to participate in this study by the clinical trial investigator based on the results of a physical examination, clinical tests, and health interview.

[0087] Exclusion criteria A clinical trial subject was excluded from the clinical trial if any of the following occurred:

[0088] (1) Those with a history of clinically significant liver, renal, neurological, respiratory, endocrine, hematological, oncological, cardiovascular, urological, and psychiatric disorders; (2) Subjects with a history of gastrointestinal disease (e.g., gastric ulcer, gastritis, stomach cramps, gastroesophageal reflux disease, Crohn's disease) or surgery (except uncomplicated appendectomy or herniotomy) that could affect the safety or pharmacokinetics of the clinical trial drug; (3) those with a history of hypersensitivity or clinically significant hypersensitivity to drugs containing proton pump inhibitor-based ingredients and other drugs (e.g., aspirin, antibiotics); (4) those who tested positive for serological tests (hepatitis B, human immunodeficiency virus (HIV), and hepatitis C tests); (5) Subjects whose blood total bilirubin, AST (GOT), and ALT (GPT) levels exceeded 1.5 times the upper limit of normal in previous screening tests, including additional tests, before randomization; (6) Subjects with a systolic blood pressure of less than 90 mmHg or more than 140 mmHg; a diastolic blood pressure of less than 50 mmHg or more than 95 mmHg; and a pulse rate of less than 45 beats / min or more than 100 beats / min measured in a seated position after at least 5 minutes of rest in a previous screening test prior to randomization. (7) Those who had anatomical abnormalities that prevented the insertion and maintenance of a pH meter catheter or who were expected to be unable to tolerate the insertion of a pH meter catheter; (8) a history of drug abuse or a positive urine screening test for a drug of abuse; (9) Persons who have taken prescription drugs (ETC) or medicines (including proton pump inhibitors, H2 receptor antagonists, antacids, etc.), or herbal medicines that affect gastric pH within 2 weeks prior to the scheduled first dose; or persons who have used over-the-counter (OTC) drugs, health functional foods, or vitamins within 1 week (however, if they meet other conditions as determined by the clinical investigator, they are eligible to participate in the clinical trial), or persons who are expected to do so; (10) Persons who have enrolled to participate in a different bioequivalence study or other clinical trial within 3 months prior to the planned first dose; (11) A person who has donated blood within two months prior to the planned first dose; or who has donated blood substance within one month prior to the first dose; or who has received a blood transfusion within one month prior to the first dose; (12) Subjects who consume excessive caffeine (more than 5 units / day) or alcohol continuously (more than 21 units / week, 1 unit = 10g of pure alcohol); or subjects who cannot abstain from alcohol during their hospitalization period. (13) Subjects who have a positive cotinine urine screening test or who are unable to quit smoking throughout the clinical trial period; (14) Those who have consumed foods containing grapefruit during the 24 hours prior to admission and before discharge and are unable to stop consuming foods containing grapefruit during this period; (15) Persons who are unable to stop consuming caffeine-containing foods (coffee, tea (black tea, green tea, etc.), carbonated drinks, coffee-flavored milk, tonics, etc.) from 24 hours before admission until discharge; (16) Individuals who are unable to use medically acceptable methods of contraception for the entire duration of the clinical trial; and (17) A person who is judged by the clinical investigator to be inappropriate for participation in the clinical trial for other reasons as a result of clinical examination.

[0089] 2. Evaluation No serious side effects or withdrawals due to side effects occurred during the course of this clinical trial. Regarding intragastric pH, the time during the observation period for intragastric pH was evaluated as the time during which intragastric pH exceeded 4.

[0090] After evaluating the pharmacokinetic parameters, the time (%) that gastric pH is maintained above 4 based on a 24 hour period is the same as shown in Table 2 below. [Table 2]

[0091] As shown in the table above, tegoprazan 25 mg was administered and changes in pH were observed for 24 hours. During the observation period for intragastric pH, the group administered tegoprazan 25 mg showed that the average time during which intragastric pH was above 4 (time pH > 4%) was at least 40% from day 1. Therefore, it was observed that administration of tegoprazan 25 mg clearly suppressed gastric acid.

[0092] Example 2 1.Selecting subjects A double-blind, randomized, and active-controlled study was designed to determine the effect of tegoprazan 25 mg for the maintenance treatment of gastroesophageal reflux disease.

[0093] Selection Criteria Unless otherwise specified, clinical trial subjects must meet all of the following inclusion criteria to participate in this clinical trial. (1) Healthy volunteers aged 20 to 75 years (inclusive); (2) Based on randomization (Visit 2), those diagnosed with erosive gastroesophageal reflux disease (LA grade A-D) by upper gastrointestinal endoscopy within 12 weeks; (3) Based on randomization (Visit 2), individuals identified as having erosive gastroesophageal reflux disease treated by upper gastrointestinal endoscopy within 7 days (those with confirmed healing of erosions due to gastroesophageal reflux disease and typical symptoms of erosive gastroesophageal reflux disease after 4 to 8 weeks of standard-dose treatment (e.g., PPI, P-CAB)); (4) based on randomization (Visit 2), those who had not been identified as having heartburn (heartburn, burning, or intrasternal pain) and acid reflux (symptoms of acid reflux or reflux of stomach contents into the esophagus) within the past 7 days; (5) Able to understand and follow instructions and participate in the clinical trial for the entire duration; (6) Individuals who voluntarily decide to participate in the clinical trial and agree to comply with the notice; and (7) Subjects who agree to use medically appropriate contraception (including those who are medically infertile) during the clinical trial.

[0094] Exclusion criteria A clinical trial subject was excluded from the clinical trial if any of the following occurred:

[0095] (1) Those who cannot undergo upper gastrointestinal endoscopy; (2) Subjects with esophageal stricture, ulcerative stricture, esophagogastric varices, long segment Barrett esophagus (LSBE) exceeding 3 cm in length, active peptic ulcer, gastrointestinal bleeding, or malignant tumors on upper gastrointestinal endoscopy; (3) Those who had "premonitory symptoms" sufficient to suggest a malignant disease of the gastrointestinal tract, such as odynophagia, severe dysphagia, bleeding, weight loss, anemia, or bloody stool (excluding hemorrhoids) (however, those who showed premonitory symptoms could be included in this clinical trial as long as the endoscopy results were negative for the presence of a tumor); (4) Individuals diagnosed with eosinophilic esophagitis, but whose esophageal biopsy showed no eosinophilic esophagitis, could be included in this clinical trial; (5) Subjects who have been diagnosed with primary esophageal motility disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), etc. within the past 3 months, or who are suspected of having IBS (excluding patients who are suspected of having IBS after examination by the clinical investigator regarding abdominal discomfort, stool consistency, bowel frequency, etc.); (6) Subjects who have previously undergone acid-suppressing surgery or gastroesophageal surgery (excluding simple perforation surgery, appendectomy, cholecystectomy, and endoscopic resection of benign tumors); (7) Persons who have developed AIDS or hepatitis (including hepatitis virus carriers: HBs-antigen positive or HCV-antibody positive) (subjects who are HCV antigen or HCV-RNA negative are eligible to participate in this clinical trial); (8) those with a history of mental illness within the past five years; (9) Persons who need to continuously take nonsteroidal anti-inflammatory drugs (NTHEs), antithrombotic drugs, etc. during the clinical trial period (however, if patients have been taking aspirin for preventive purposes only before participating in this clinical trial, they may take low-dose aspirin (100 mg or less per day)); (10) Persons receiving HIV protease inhibitors (atazanavir and nelfinavir) or preparations containing rilpivirine; (11) Pregnant or breastfeeding women; (12) Those who showed clinically significant abnormal values in the screening test; - AST, ALT, ALP, γ-GT, and total bilirubin values ≥2 times the upper limit of normal (UNL) for each test setting; - BUN and creatinine values ≥ 1.5 times the UNL for each test setting; (13) Patients who showed clinically significant abnormal electrocardiogram (ECG) (major arrhythmia, multiple PVCs, second-degree atrioventricular block abnormalities, etc.); (14) People with Zollinger-Ellison syndrome; (15) Persons with a history of malignant tumor within the past 5 years (however, this clinical trial may include persons who have been determined to have complete remission (CR, pCR) from their tumor, have been free of recurrence for at least 5 years from the date of such determination, and have had their tumor completely removed by endoscopic resection and have been free of recurrence for at least 3 years); (16) Those who showed clinically significant disorders in the liver, kidney, cardiovascular, respiratory, endocrine, and central nervous systems; (17) Subjects with a history of hypersensitivity to any component of the clinical trial drug (including expellants or antacids) or benzimidazoles; (18) Persons who are scheduled to undergo surgery requiring hospitalization or surgical treatment during participation in this clinical trial; (19) Persons who have participated in any form of another clinical trial within the past 12 weeks based on the start date of screening (Visit 1) (however, this clinical trial may allow participants who have previously participated in a non-interventional trial (such as an observational study or questionnaire study) or who are currently participating in a non-interventional trial and who the clinical trial investigator determines will not affect the efficacy and safety of this clinical trial, or who have completed a consent form to participate in another clinical trial but then dropped out of the administration of the clinical trial drug and treatment screening);

[0096] 2. Clinical trial design The clinical trial is conducted in a double-blind, randomized, active-controlled, and multicenter clinical trial manner, and the clinical trial can be diagrammed as shown in Figure 1.

[0097] Subjects who visited the clinical trial were assigned a screening number in the order in which they consented on the first day of the visit (Visit 1), and subjects who met the inclusion criteria were selected by undergoing screening tests, confirming their medical history, and conducting gastroscopy. After selection was completed, the clinical trial subjects were randomly assigned (Visit 2) and divided into two groups.

[0098] Participants were assigned using stratified block randomization based on LA grade determined by upper gastrointestinal endoscopy performed within 12 weeks before randomization at Visit 2. Each group received the drug for 24 weeks.

[0099] 3. Dosage and Administration Clinical trial subjects received tablets and capsules as shown in Table 3. [Table 3]

[0100] As shown in the table above, the test group was orally administered tegoprazan 25 mg tablets (Preparation Example 1) / lansoprazole 15 mg placebo (Preparation Example 4), and the control group was orally administered tegoprazan 25 mg placebo (Preparation Example 2) / lansoprazole 15 mg capsules (Preparation Example 3).

[0101] Subjects randomly assigned to each group took the prescribed clinical trial medication once daily on the first day of prescription. A clinical trial subject diary was kept from the day they started taking the clinical trial medication.

[0102] If moderate to severe symptoms of heartburn or acid reflux were observed for three consecutive days during the administration of the clinical trial drug, endoscopic examination was performed to determine whether erosive reflux disease had recurred. If endoscopic examination confirmed recurrence of erosive reflux, the corresponding subject was terminated from the clinical trial. However, if symptoms were alleviated to some extent by taking rescue medication (antacids) instead of PPIs, the clinical trial was continued with the rescue medication (antacids) limited to a maximum of once daily, not more than twice weekly (however, rescue medication (antacids) were not taken within one hour before or after taking the clinical trial drug).

[0103] During the 4-week (Visit 3), 12-week (Visit 4), and 24-week (Visit 5) visits, subjects visited on an empty stomach without taking any clinical trial medication. After undergoing scheduled tests, they were prescribed a new dose of the same medication, which they began taking on that day. They were then examined at the 24-week visit (Visit 5) and the treatment was discontinued.

[0104] Four weeks after administration of the clinical trial drug (Visit 3), no endoscopy was performed, but clinical tests (blood tests, blood chemistry tests, blood coagulation tests, urinalysis, hepatitis tests, etc.) and symptom evaluation were performed. At 12 weeks (Visit 4) and 24 weeks (Visit 5), upper gastrointestinal endoscopy was performed to check for recurrence of erosions, and clinical tests and symptom evaluation were also performed. After receiving the clinical trial drug for up to 24 weeks, clinical trial subjects entered a safety follow-up (f / u) period, during which f / u was performed (by phone or in person) 2 weeks after the last dose.

[0105] 4. Evaluation Method A. Primary efficacy evaluation: endoscopic remission maintenance rate at 24 weeks

[0106] [1] Endoscopic remission: No recurrence of erosions (LA grade A-D) is observed by upper gastrointestinal endoscopy during the maintenance period (24 weeks).

[0107] [2] Maintenance rate of endoscopic remission after 24 weeks (%) = (Number of clinical trial subjects who did not experience recurrence of erosions during the maintenance period / Number of clinical trial subjects who underwent upper gastrointestinal endoscopy during the maintenance period after administration of the clinical trial drug) x 100

[0108] However, if recurrence was confirmed endoscopically, the clinical trial subject was discontinued at the time of confirmation and was included in the total number of clinical trial subjects.

[0109] - If a clinical trial subject who did not have recurrent erosions observed by upper gastrointestinal endoscopy did not visit the scheduled visit (>168+5 days) 24 weeks (±5 days) after administration of the clinical trial drug, this case was included in the endoscopic remission maintenance rate at 24 weeks.

[0110] B. Secondary efficacy results: endoscopic remission maintenance rate after 12 weeks

[0111] [1] Endoscopic remission: No recurrence of erosions (LA grade A-D) is observed by upper gastrointestinal endoscopy during the maintenance period (12 weeks).

[0112] [2] Maintenance rate of endoscopic remission after 12 weeks (%) = (Number of clinical trial subjects who did not experience recurrence of erosions during the maintenance period / Number of clinical trial subjects who underwent upper gastrointestinal endoscopy during the maintenance period after administration of the clinical trial drug) x 100

[0113] However, if recurrence was confirmed endoscopically, the clinical trial subject was discontinued at the time of confirmation and was included in the total number of clinical trial subjects.

[0114] - If a clinical trial subject who did not have recurrent erosions observed by upper gastrointestinal endoscopy did not visit the scheduled date (>84+5 days) 12 weeks (±5 days) after administration of the clinical trial drug, this case was included in the endoscopic remission maintenance rate at 12 weeks.

[0115] C. Additional Efficacy Results 1) The proportion of clinical trial subjects free of major symptoms (heartburn and / or acid reflux) at 4, 12, and 24 weeks

[0116] [1] Percentage of clinical trial subjects without major symptoms (heartburn or acid reflux) Percentage of clinical trial subjects without primary symptoms = (Number of clinical trial subjects without primary symptoms / Number of clinical trial subjects with symptoms assessed during the maintenance period after administration of the clinical trial drug) x 100

[0117] [2] Percentage of clinical trial subjects who did not experience heartburn Percentage of clinical trial subjects without heartburn = (number of clinical trial subjects without heartburn / number of clinical trial subjects with symptom assessment during the maintenance period after administration of clinical trial drug) x 100

[0118] [3] Percentage of subjects without acid reflux Percentage of clinical trial subjects without acid reflux = (Number of clinical trial subjects without acid reflux / Number of clinical trial subjects with symptom assessment during the maintenance period after administration of clinical trial drug) x 100

[0119] 2) Symptom assessment by clinical trial subjects' diary at 4, 12, and 24 weeks

[0120] [1] Number of days without major symptoms (heartburn or acid reflux) Number of days without main symptoms = (number of days without main symptoms / number of days when main symptoms were assessed) x 100

[0121] [2] Number of days without heartburn Number of days without heartburn = (number of days without main symptoms / number of days with main symptoms) x 100

[0122] [3] Number of days without acid reflux Number of days without acid reflux = (number of days without main symptoms (daytime + nighttime) / number of days with main symptoms) x 100

[0123] Symptom assessments at each visit and by clinical trial subject diary were assessed using the following scores: [Table 4]

[0124] 3) GERD-HRQL assessment : Mean change in GERD-HRQL (gastroesophageal reflux disease health-related quality of life) total score after 4, 12, and 24 weeks compared to baseline before treatment

[0125] Subjects were asked to complete a questionnaire at each visit according to Velanovich V. (The development of the GERD-HRQL symptom severity instrument. DisEsophagus 2007;20:130-4). The GERD-HRQL score is defined as: [Table 5]

[0126] D. Subgroup Analysis and Evaluation 1) Maintenance rate of endoscopic remission after 24 weeks by LA grade 2) Maintenance rate of endoscopic remission after 24 weeks according to the presence of H. pylori infection 3) Maintenance rate of endoscopic remission after 24 weeks according to the use of rescue medication (antacids) 4) Maintenance rate of endoscopic remission by CY2C19 genotype -Normal active type (Extensive Metaboliser, EM) -Intermediate Metabolizer (IM) -Low activity type (Poor Metaboliser, PM)

[0127] E. Safety Assessment Adverse reactions, laboratory tests (hematology, blood chemistry, blood coagulation, urinalysis), vital signs (sitting blood pressure, heart rate, temperature), ECG, central laboratory tests (gastrin, pepsinogen I / II, vitamin B12, folate, iron, magnesium)

[0128] 5. Evaluation Results A. Evaluation of symptoms after 4 weeks of treatment Subjects in both the test and control groups who received tegoprazan 25 mg after four weeks of drug administration showed a maintenance effect.

[0129] Notably, all subjects in the test group (treated with tegoprazan 25 mg) and the control group (treated with lansoprazole 15 mg) responded to a symptom assessment four weeks after the drug's administration that they had not experienced any symptoms of heartburn or acid reflux during the four weeks they were taking the drug.

[0130] B. Endoscopy results after 12 weeks of administration After 12 weeks of drug administration, the maintenance rate of endoscopic remission was evaluated in the test and control groups (secondary efficacy outcome). A maintenance effect was observed in subjects administered tegoprazan 25 mg.

[0131] Notably, after 12 weeks of drug administration, erosions were observed by upper gastrointestinal endoscopy in only one subject out of a total of 37 subjects in the test group (administered tegoprazan 25 mg; at least 17 subjects) and the control group (administered lansoprazole 15 mg); i.e., no erosions were observed by upper gastrointestinal endoscopy in the remaining 36 clinical trial subjects.

[0132] Therefore, it was observed that administration of 25 mg of tegoprazan effectively inhibited the recurrence of gastroesophageal reflux disease.

[0133] C. Safety Assessment No adverse effects were observed during 4 to 12 weeks of treatment based on safety assessment of clinical tests (hematology, blood chemistry, blood coagulation, and urinalysis), vital signs (sitting blood pressure, heart rate, and temperature), ECG tests, and central laboratory tests (gastrin, pepsinogen I / II, vitamin B12, folic acid, iron, and magnesium).

Claims

1. A pharmaceutical composition for preventing the recurrence of gastroesophageal reflux disease, the pharmaceutical composition comprising 25 mg of tegoprazan, a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof, for which no side effects were observed in a safety evaluation of gastrin. [Chemical formula 1]

2. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered to a subject who has been diagnosed with gastroesophageal reflux disease and subsequently treated for gastroesophageal reflux disease.

3. The pharmaceutical composition of claim 2, wherein the subject has been diagnosed with gastroesophageal reflux disease one or more times prior to administration of the pharmaceutical composition.

4. The pharmaceutical composition of claim 2, wherein the subject was diagnosed with gastroesophageal reflux disease before administration of the pharmaceutical composition and then does not exhibit symptoms of heartburn and gastric acid reflux upon administration of the drug, and the drug is a gastric acid secretion inhibitor.

5. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is administered to a subject who has been diagnosed with erosive gastroesophageal reflux disease and subsequently treated for erosive gastroesophageal reflux disease.

6. The pharmaceutical composition according to claim 5, wherein the subject was diagnosed with erosive gastroesophageal reflux disease before administration of the pharmaceutical composition and the erosive gastroesophageal reflux disease was subsequently confirmed to be cured by administration of a drug, and the drug is a gastric acid secretion inhibitor.

7. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is administered to a subject who has been diagnosed with non-erosive gastroesophageal reflux disease and subsequently treated for non-erosive gastroesophageal reflux disease.

8. The pharmaceutical composition according to claim 7, wherein the subject was diagnosed with non-erosive gastroesophageal reflux disease before administration of the pharmaceutical composition and the non-erosive gastroesophageal reflux disease was subsequently confirmed to be cured by administration of a drug, and the drug is a gastric acid secretion inhibitor.

9. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered once daily for 4 to 52 weeks.

10. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered once daily for 4 to 24 weeks.

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