Method for treating gastrointestinal diseases using 6-methoxypyridin-3-yl derivative

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases, comprising a therapeutically effective amount of a compound represented by chemical formula 1, wherein provision is made of dosages and administration regimens of the composition suitable for achieving optimal prophylactic and therapeutic effects in a subject with a gastrointestinal disease. [Chemical formula 1]

Description

Method for treating gastrointestinal diseases comprising 6-methoxypyridin-3-yl derivatives

[0001] The present invention relates to an appropriate dosage and administration of a pharmaceutical composition for preventing or treating gastrointestinal diseases comprising a 6-methoxypyridin-3-yl derivative.

[0002] Proton pump inhibitors (PPIs), such as omeprazole, which suppress gastric acid secretion, are widely used in clinical settings. However, existing PPIs present problems in terms of efficacy and side effects. Specifically, existing PPIs are unstable under acidic conditions, so they are often formulated as enteric-coated preparations. In these cases, the onset of action requires several hours, and continuous administration requires approximately five days to achieve maximum efficacy. Furthermore, existing PPIs exhibit variable therapeutic effects due to polymorphisms in metabolic enzymes and drug interactions with drugs such as diazepam, requiring improvement. Furthermore, PPIs are prodrugs activated by gastric acid and act only on the active proton pump. This delays the time to peak effect, makes them less effective in suppressing nocturnal acid secretion, and requires them to be taken before meals. Additionally, PPIs are mainly metabolized through the CYP2C19 enzyme, and there is a large difference in efficacy between individuals due to genetic polymorphism of the CYP2C19 enzyme.

[0003] Potassium-competitive acid blockers (P-CABs) are attracting attention to improve the shortcomings of proton pump inhibitors (PPIs). Potassium-competitive acid blockers reversibly and competitively bind to the proton pump (H+ / K+-ATPase), an enzyme involved in the final stage of gastric acid secretion in gastric parietal cells, and potently and rapidly inhibit gastric acid secretion. These P-CAB agents show stronger inhibition at normal gastric acidity (pH 1-3) than PPI agents. However, pharmacological activity that decreases as pH increases is required for gastric P-CAB agents. However, some P-CAB agents maintain pharmacological activity even at high pH, ​​and some related side effects have been reported. Additionally, because P-CAB preparations are primarily metabolized through the CYP3A4 enzyme, there is relatively little difference in efficacy between individuals, and concerns about interactions with drugs metabolized through the CYP2C19 enzyme are relatively low.

[0004] Against this backdrop, numerous attempts are being made to develop new P-CAB drugs. For example, Korean Patent Registration No. 10-2432523 discloses a novel P-CAB inhibitor that exhibits excellent acid secretion suppression effects.

[0005] The present inventors developed a pharmaceutical composition for preventing or treating gastrointestinal diseases comprising the above P-CAB inhibitor compound or a pharmaceutically acceptable salt thereof, and completed the present invention by identifying an appropriate dosage for the composition to exhibit an optimal preventive or therapeutic effect.

[0006] The present invention provides a pharmaceutical composition for preventing or treating gastrointestinal diseases, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0007] The present invention provides an appropriate dosage and method of use of a pharmaceutical composition for preventing or treating gastrointestinal diseases, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0008] The present invention relates to a pharmaceutical composition for preventing or treating gastrointestinal diseases, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and provides appropriate usage and dosage of the composition.

[0009] By using the compound represented by the chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof in the dosage and method provided in the present invention, there is an advantage in that an optimal preventive or therapeutic effect can be obtained for gastrointestinal diseases such as diseases related to gastric acid secretion, reflux esophagitis, or erosive esophagitis.

[0010] The present invention provides a pharmaceutical composition for preventing or treating gastrointestinal diseases, which comprises administering a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof in a total amount of 10 mg to 80 mg once or twice a day.

[0011] [Chemical Formula 1]

[0012]

[0013] In the present invention, the compound represented by the chemical formula 1 is 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine, which is a substance described in Korean Patent Registration No. 10-2432523.

[0014] The compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof exhibits excellent therapeutic efficacy for reflux esophagitis or erosive esophagitis based on a novel dosage and method.

[0015] In the present invention, the compound represented by the above chemical formula 1 may exist in the form of a "pharmaceutically acceptable salt." As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt that has an effective effect that is relatively non-toxic and harmless to a patient, and whose side effects due to the salt do not diminish the beneficial effects of the compound of the chemical formula 1.

[0016] The above "pharmaceutically acceptable salt" means a salt commonly used in the pharmaceutical industry, and may be, for example, an inorganic ion salt made of calcium, sodium, etc., an inorganic acid salt made of phosphoric acid, hydrobromic acid, iodic acid, sulfuric acid, etc., an organic acid salt made of acetic acid, trifluoroacetic acid, citric acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, carbonic acid, vanillic acid, etc., a sulfonic acid salt made of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc., an amino acid salt made of glycine, arginine, etc., and an amine salt made of trimethylamine, triethylamine, etc.

[0017] Preferably, the pharmaceutically acceptable salt may be any one selected from the group consisting of hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid and methanesulfonic acid.

[0018] More preferably, the pharmaceutically acceptable salt may be fumaric acid.

[0019] Accordingly, the compound according to the present invention may have a structure represented by the following chemical formula 2.

[0020] [Chemical Formula 2]

[0021]

[0022] The pharmaceutical composition of the present invention can be formulated according to conventional methods and prepared as an oral administration preparation. For example, the pharmaceutical composition of the present invention can be prepared as an oral administration preparation.

[0023] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are formulated by mixing the above composition with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0024] The composition of the present invention can be administered orally in the form of tablets, pills, powders, granules, or capsules. Preferably, it can be administered in the form of tablets or capsules. Tablets are more preferred.

[0025] The compound represented by chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can prevent or treat gastrointestinal diseases by administering a total of 10 mg to 80 mg once or twice a day to a subject in need of prevention or treatment of gastrointestinal diseases.

[0026] For example, based on a normal adult weighing about 60 kg, the total daily dose of the compound of chemical formula 1 may be administered orally at a total of 10 to 80 mg, and the above application may be administered once a day or divided into two times. Preferably, it may be administered once a day.

[0027] The composition may be administered once daily for one to eight weeks. More specifically, the composition may be administered once daily for one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks. Any period between one and eight weeks is included within the scope of the present invention.

[0028] The composition may be administered once daily in a dosage of 10 to 80 mg. For example, the dosage may be 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg. Preferably, the dosage may be 20 mg to 40 mg.

[0029] More preferably, the composition may be administered at 20 mg once daily.

[0030] More preferably, the composition may be administered once daily at a dose of 40 mg. The composition according to the present invention may be administered once or twice daily at any time, regardless of whether or not the person eats or the time of the meal. In addition, the composition may be administered once daily before a meal. Furthermore, more preferably, the composition may be administered once daily 30 minutes to 1 hour before a meal. Furthermore, the action of the drug according to the present invention can exhibit excellent therapeutic efficacy even with a single dose daily due to its long half-life.

[0031] More preferably, it may be administered at 20 mg once daily for at least 3, 4, 5, 6, 7, or 8 weeks. More preferably, it may be administered at 20 mg once daily for 4 weeks. More preferably, it may be administered at 20 mg once daily for 5 weeks. More preferably, it may be administered at 20 mg once daily for 6 weeks. More preferably, it may be administered at 20 mg once daily for 7 weeks. More preferably, it may be administered at 20 mg once daily for 8 weeks.

[0032] More preferably, it may be administered at 40 mg once daily for at least 3, 4, 5, 6, 7, or 8 weeks. More preferably, it may be administered at 40 mg once daily for 4 weeks. More preferably, it may be administered at 40 mg once daily for 5 weeks. More preferably, it may be administered at 40 mg once daily for 6 weeks. More preferably, it may be administered at 40 mg once daily for 7 weeks. More preferably, it may be administered at 40 mg once daily for 8 weeks.

[0033] If necessary, the preventive and therapeutic methods according to the present invention may be combined with treatment and maintenance therapies.

[0034] More specifically, for the treatment therapy, it may be administered at 40 mg once a day for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks. More preferably, it may be administered at 40 mg once a day for at least 2 weeks, 3 weeks, or 4 weeks. More preferably, it may be administered at 40 mg once a day for at least 3 weeks or 4 weeks. More preferably, it may be administered at 40 mg once a day for 4 weeks. Then, for the maintenance therapy, the amount of the administered drug may be reduced to produce a state of continuous remission. In the present invention, maintenance therapy is a treatment method that is administered over a long period of time to prevent the recurrence of a disease that has been alleviated after the initial treatment. More specifically, the maintenance therapy according to the present invention is continuous maintenance therapy, which is a therapy that continuously administers a lower dose than the initial administration dose so that the state of complete disappearance or reduction of symptoms can be maintained.

[0035] Accordingly, maintenance therapy may be administered following the above treatment regimen. This refers to administration at a reduced dosage after the completion of the above treatment regimen. More specifically, it may be administered at a dose of 20 mg once daily for at least 1, 2, 3, 4, or 5 weeks following the treatment regimen. More preferably, it may be administered at a dose of 20 mg once daily for at least 1, 2, 3, or 4 weeks.

[0036] Treatment and maintenance therapy can also be administered in conjunction with the following schedule. The combination of treatment and maintenance therapy mentioned below is an example of a combination that can prevent relapse and maintain remission after treatment:

[0037] 40 mg once daily as treatment for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks, followed by 20 mg once daily as maintenance therapy for at least 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks following treatment;

[0038] 40 mg once daily as a treatment regimen for at least 2, 3, or 4 weeks, followed by 20 mg once daily as a maintenance regimen for at least 1, 2, 3, or 4 weeks following the treatment regimen;

[0039] Administered as a treatment regimen at 40 mg once daily for at least 3 weeks, or 4 weeks, followed by maintenance therapy at 40 mg once daily for 1 week, 2 weeks, 3 weeks, or 4 weeks.

[0040] By using the pharmaceutical composition according to the present invention in the above-mentioned dosage and method, an optimal preventive or therapeutic effect can be obtained in patients with gastrointestinal diseases, particularly patients with reflux esophagitis and / or erosive esophagitis.

[0041] In the present invention, the gastrointestinal disease may be a gastrointestinal ulcer, a gastrointestinal inflammatory disease, or a gastric acid-related disease.

[0042] The above gastrointestinal ulcer, gastrointestinal inflammatory disease or gastric acid-related disease may be at least one selected from the group consisting of peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, acute stress ulcer, Zollinger-Ellison syndrome, Helicobacter pylori infection, gastritis, erosive esophagitis, non-erosive esophagitis, reflux esophagitis, inflammatory bowel disease, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, gastric MALT lymphoma, hyperacidity, and upper gastrointestinal bleeding due to invasive stress.

[0043] Preferably, the pharmaceutical composition of the present invention can be usefully used for the prevention or treatment of erosive esophagitis or reflux esophagitis. More preferably, it can be usefully used for the prevention or treatment of erosive esophagitis.

[0044] In the present invention, a subject requiring prevention or treatment of a gastrointestinal disease may be a patient with erosive esophagitis. Such patients with erosive esophagitis may be classified based on the Los Angeles classification (LA grade).

[0045] The above LA classification system is a classification system that can diagnose erosive gastroesophageal reflux disease through upper gastrointestinal endoscopy. In the LA classification system, grade A refers to a case where there is one or more mucosal defects in the esophagus that are less than 5 mm in length, grade B refers to a case where there is one or more mucosal defects in the esophagus that are 5 mm or more in length, grade C refers to a case where the mucosal defects of the esophagus are combined but do not exceed 75% of the esophageal circumference, and grade D refers to a case where the mucosal defects of the esophagus are combined and exceed 75% of the esophageal circumference.

[0046] In the present invention, erosive esophagitis may be erosive gastroesophageal reflux disease classified as grade A or higher in the LA classification.

[0047] That is, in the present invention, erosive esophagitis can be defined as a case where there is one or more mucosal defects in the esophagus that are less than 5 mm in length, and a patient with erosive esophagitis can be defined as a patient with one or more mucosal defects in the esophagus that are less than 5 mm in length.

[0048] In the present invention, erosive esophagitis may be erosive gastroesophageal reflux disease classified as grade B or higher in the LA classification.

[0049] In the present invention, erosive esophagitis may be erosive gastroesophageal reflux disease classified as grade C or higher in the LA classification.

[0050] In the present invention, erosive esophagitis may be erosive gastroesophageal reflux disease classified as grade D or higher in the LA classification system.

[0051] The term "prevention or treatment" used in the present invention refers to any act of inhibiting or delaying the onset of a gastrointestinal disease by using the pharmaceutical composition or combination according to the present invention, and in particular, "treatment" refers to any act of improving or beneficially changing a gastrointestinal disease by using the composition.

[0052] The present invention provides a method for preventing or treating a gastrointestinal disease, comprising administering to a subject in need of prevention or treatment of a gastrointestinal disease a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, once or twice a day, in a total amount of 10 mg to 80 mg.

[0053] In another aspect, the present invention relates to a composition for use in the prevention or treatment of gastrointestinal diseases by administering a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof in a total of 10 mg to 80 mg once or twice a day.

[0054] In another aspect, the present invention relates to the use of a composition comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing or treating gastrointestinal diseases by administering a total of 10 mg to 80 mg once or twice daily.

[0055] The above-mentioned methods, compositions and uses, including the aforementioned treatment and maintenance therapy, can be equally applied to each of the above.

[0056] The composition and treatment method of the present invention can exhibit the following effects:

[0057] 1) Improvement of mucosal defects after administration

[0058] 2) Improvement in frequency and severity of main symptoms on the reflux disease symptom assessment (RDQ) after administration

[0059] 3) Improvement in the total score of the quality of life assessment (GERD-HRQL) after administration

[0060] 4) Improvement of symptoms as assessed by the subject's diary after administration

[0061] - Disappearance of the main symptoms of gastroesophageal reflux disease

[0062] - Increased proportion of days without major symptoms of GERD (daytime, nighttime, all day)

[0063] The above-mentioned therapeutic effects may be maintained for at least 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks or more after drug administration.

[0064] Within the dosage regimen according to the present invention, the ratio of time during which the intragastric acidity is maintained at pH 4 or higher is high, so that a strong gastric acid suppression effect can be exhibited.

[0065] Additionally, it has no side effects associated with atrophic gastritis and can increase gastrin levels. Increased gastrin may support the regeneration and protection of gastric mucosal cells, positively impacting gastrointestinal function.

[0066] Moreover, it possesses the advantage of demonstrating superior therapeutic efficacy without the issue of DDI, making it highly applicable for combination therapy with other drugs. Accordingly, it can enhance therapeutic efficacy while exhibiting the desired gastric acid suppression effect without adverse side effects, even when used in combination with drugs such as midazolam, atorvastatin, amlodipine, amoxicillin, and clarithromycin. In other words, the drug's superior efficacy can also be confirmed from a pharmacokinetic perspective.

[0067] The composition of the present invention is expected to exhibit therapeutic efficacy in a subject according to the above-mentioned evaluation indicators.

[0068] In addition, the composition of the present invention is expected to exhibit sufficient safety in safety evaluations (specifically, evaluation indicators such as adverse events, laboratory tests, vital signs, physical examinations, and electrocardiogram tests) for the above usage and dosage regimen.

[0069] The present invention relates to a pharmaceutical composition for preventing or treating gastrointestinal diseases, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and by using the composition in an appropriate dosage and manner, an optimal preventive or therapeutic effect can be obtained for diseases related to gastric acid secretion, particularly reflux esophagitis or erosive esophagitis.

[0070] Figure 1 shows the efficacy and safety test schedule for patients with erosive esophagitis of the compound of chemical formula 1.

[0071] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only to illustrate the present invention and the scope of the present invention is not limited to the following examples.

[0072] Example 1-1. PK / PD modeling and simulation using nonclinical study results.

[0073] In order to predict the pharmacokinetics and effective dose in humans by utilizing the nonclinical study results of the compound of the present invention, PK / PD modeling and simulation using the allometric scaling technique of nonclinical animal species were performed.

[0074] A total of four simulations were performed based on a combination of two PK indices (BrW-, MLP-corrected allometry) and two PD structural models (effect compartment, turnover model) to predict human gastric pH profiles for up to 168 hours after once-daily administration of 0.1-40 mg ID120040002.

[0075] The target pH on Days 1 and 7 is ≥4.0, and the minimum effective dose to reach the target pH in each simulation scenario is as follows.

[0076] Simulation Results Human Efficacy Dose (mg) Day 1 Day 7 #1. PK: BrW-corrected - PD: effect compartment model 105 #2. PK: MLP-corrected - PD: effect compartment model 155 - 10 #3. PK: BrW-corrected - PD: turnover model 105 - 10 #4. PK: MLP-corrected - PD: turnover model 1510

[0077] That is, as a result of predicting the effective dose in humans through modeling using nonclinical PK / PD results, it was confirmed that the effective dose could be from 5 mg to 10 mg, and 5 mg was selected as the starting dose.

[0078] Example 1-2. Safety testing and pharmacological efficacy investigation of the compound of chemical formula 1 in healthy subjects.

[0079] To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic characteristics of the compound of the present invention after single and repeated administration at different doses, a randomized, double-blind, partially open-label, placebo- and active-controlled, stepwise dose-escalation phase 1 clinical trial was conducted on healthy adults.

[0080] Safety, tolerability, and pharmacokinetics / pharmacodynamics were evaluated in a single, double-blind, dose-escalation study involving 48 healthy adult volunteers in Korea. The compound was administered in doses of 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg, along with placebo, in a fasting state for at least 10 hours. Furthermore, a 7-day, repeated dose-escalation study was conducted in 38 healthy adult volunteers in Korea at doses of 20 mg, 40 mg, or 80 mg.

[0081] As a result of the evaluation of pharmacokinetic and pharmacodynamic characteristics, the blood concentration of the compound increased in proportion to the dose up to 40 mg administration, and in a single-dose test, the 24-hour gastric acid secretion inhibition effect was shown to be proportional to the dose, and in a repeated-dose test, it was confirmed that the gastric acid secretion inhibition pattern was maintained even at the 7th day of clinical trial drug administration. In addition, it was confirmed that the compound appropriately maintained the pH 4 or higher for a time period at 20 mg or more.

[0082] Safety assessment results showed that no severe adverse events of Grade 3 or higher or unexpected adverse events occurred during the clinical trial. Therefore, based on these results, the appropriate therapeutic exploration doses for Phase 2 clinical trials were selected as 20 mg and 40 mg.

[0083] Example 2. Confirmation of the effect on maintaining intragastric acidity at pH 4 or higher.

[0084] The "proportion of time during which intragastric pH remained above 4" was determined at therapeutic doses of 20 mg and 40 mg. Specifically, the proportion of time during which intragastric pH remained above 4 within 24 hours from the time of administration was measured. The results are presented in Table 2.

[0085] [Multiple-dose test] Percentage of time spent maintaining pH 4 or higher within 24 hours

[0086] TreatmentDay -1Mean (SD)Day 1Mean (SD)Day 7Mean (SD)ID120040002 20 mg (N=7)8.19 (4.77)30.06 (15.21)56.29 (13.43)ID120040002 40 mg (N=8)6.32 (4.60)65.54 (20.90)89.72 (8.98)Tegoprazan 50 mg (N=8)9.31 (4.51)41.66 (8.04)46.68 (19.66)Pooled Placebo (N=6)10.66 (3.60)10.32 (3.06)7.93 (2.42)

[0087] SD: Standard Deviation

[0088] As shown in Table 2, the 20 mg and 40 mg doses demonstrated very high rates of time spent maintaining intragastric pH above 4. This effect was particularly pronounced at 40 mg, demonstrating its suitability for use at this dose. This suggests superior efficacy compared to known acid-suppressing drugs.

[0089] That is, maintaining the intragastric pH above 4 for an extended period of time can provide various clinical benefits. This sustained acid suppression promotes mucosal healing by creating an environment suitable for the recovery of mucosal damage in the stomach and esophagus, effectively controlling heartburn and reflux symptoms associated with GERD (gastroesophageal reflux disease). Furthermore, consistent gastric acid suppression can reduce problems such as nocturnal acid secretion. This unexpectedly excellent effect, not observed in existing P-CAB-based drugs, confirms the excellent efficacy of the dosage regimen according to the present invention.

[0090] Example 3. Efficacy and safety test of the compound of chemical formula 1 on patients with erosive esophagitis

[0091] Example 3-1. Efficacy and safety test design

[0092] In order to explore the efficacy and safety of the compound of the present invention according to dose and to select an appropriate therapeutic dose, a multicenter, randomized, double-blind, active-controlled, parallel-group phase 2 clinical trial was conducted on patients with erosive gastroesophageal reflux disease (ERD).

[0093] A total of 147 subjects were selected for the study, with at least 49 randomly assigned to each group. Subjects were administered 1 to 2 tablets (4 tablets if placebo included) orally once daily before meals for up to 8 weeks, starting the day after receiving the clinical trial drug, according to their randomized treatment group. The clinical trial drug dosages by treatment group are as follows:

[0094] Administration group Clinical trial drug Test group 1 Compound of chemical formula 1 20 mg ● 2 tablets / □ 1 tablet / ◇ 1 tablet Test group 2 Compound of chemical formula 1 40 mg ○ 2 tablets / ■ 1 tablet / ◇ 1 tablet Control group Esomeprazole 40 mg ○ 2 tablets / □ 1 tablet / ◆ 1 tablet ●: Compound of chemical formula 1 10 mg ■: Compound of chemical formula 1 40 mg ◆: Esomeprazole 40 mg ○: Placebo for 10 mg of compound of chemical formula 1 □: Placebo for 40 mg of compound of chemical formula 1 ◇: Placebo for 40 mg of esomeprazole

[0095] That is, in test group 1, two 10 mg tablets of the compound of chemical formula 1, one placebo tablet for 40 mg of the compound of chemical formula 1, and one placebo tablet for 40 mg of esomeprazole were administered orally once a day before meals for up to 8 weeks; in test group 2, one 40 mg tablet of the compound of chemical formula 1, two placebo tablets for 10 mg of the compound of chemical formula 1, and one placebo tablet for 40 mg of esomeprazole were administered orally. In the control group, one 40 mg tablet of esomeprazole, two placebo tablets for 10 mg of the compound of chemical formula 1, and one placebo tablet for 40 mg of the compound of chemical formula 1 were administered orally once a day before meals for up to 8 weeks.

[0096] Subjects were contacted by phone one week after administration of the investigational drug (Visit 3), and after four weeks of administration, they visited the study site to undergo upper gastrointestinal endoscopy to check for improvement. Subjects who achieved complete response (CR: no mucosal defects observed in upper gastrointestinal endoscopy) underwent a Safety F / U two weeks later, and subjects who did not achieve complete response (CR) were administered the investigational drug for an additional four weeks (a total of eight weeks of administration) and then visited the study site to undergo an upper gastrointestinal endoscopy. Regardless of whether they achieved complete response (CR), a Safety F / U was performed two weeks later. During the treatment period, subjects visited the study site at four-week intervals (Visit 4, Visit 5) to undergo planned efficacy and safety evaluations. The relevant experimental schedule is shown in Figure 1.

[0097] Example 3-2. Target patient group

[0098] The test was conducted on subjects who met the following subject selection criteria and did not meet the subject exclusion criteria.

[0099] ●Test subject selection criteria

[0100] 1) Adult male or female aged 19 to 75 as of the date of written consent

[0101] 2) Those diagnosed with erosive gastroesophageal reflux disease grade A or higher according to the Los Angeles classification system (LA grade) through an upper gastrointestinal endoscopy at the same institution within 5 weeks prior to administration of the clinical trial drug.

[0102] [LA classification]

[0103]

[0104] 3) Those who experienced heartburn (heartburn or burning sensation inside the breastbone, pain inside the breastbone) and / or acid reflux (symptoms of acid coming up or stomach contents flowing back into the esophagus) within 14 days of Visit 2

[0105] 4) Female or male subjects who fall under one of the following during the clinical trial period:

[0106] ① The female subject or the female partner of the male subject is in menopause (non-therapy-induced amenorrhea for 12 months or more)

[0107] ② Infertility due to surgery of the female subject or the female partner of the male subject (hysterectomy, bilateral oophorectomy, bilateral salpingectomy, etc.)

[0108] ③ Those who agreed to absolute abstinence during the clinical trial period

[0109] [Intermittent abstinence (e.g., using the ovulatory period, symptothermal method, or post-ovulatory period) or withdrawal ejaculation are not considered if abstinence is agreed upon]

[0110] ④ If the female subject or the female partner of the male subject is a woman of childbearing age (WOCBP), the person who agrees to use the following contraception method.

[0111] - Female subjects or female partners of male subjects: hormonal contraceptives (oral hormonal contraceptives, injections, subcutaneous implants), intrauterine devices (copper loops, hormone-containing intrauterine systems), sterilization (tubal ligation, etc.), physical barrier methods (female condoms (femidoms))

[0112] - For men: sterilization (vasectomy), physical barrier method (male condom)

[0113] 5) A person who can complete the questionnaire and subject diary

[0114] 6) A person who understands the information provided to him / her and can voluntarily sign the written consent form.

[0115] ●Exclusion criteria for test subjects

[0116] [Digestive System Related]

[0117] 1) Those with esophageal motility disorders and lesions other than the selection criteria confirmed or accompanied by esophageal varices or upper gastrointestinal endoscopy during screening (Visit 1) (e.g., Barrett's esophagus, gastroesophageal varices, esophageal stricture, ulcer stricture, active peptic ulcer, gastrointestinal bleeding, gastroesophageal tumor, etc.)

[0118] 2) Those who have undergone gastric acid suppression surgery, gastric or esophageal surgery, or gastrointestinal tumor resection (e.g., gastrectomy, colectomy, etc.). However, registration is possible if the following applies:

[0119] ① Appendectomy, cholecystectomy, polypectomy

[0120] ② In the case of endoscopic resection of malignant tumors or endoscopic resection of early gastric cancer (EMR, ESD), if the patient has been cured and has not recurred for more than 5 years from the date of diagnosis

[0121] 3) Those diagnosed with Zollinger-Ellison syndrome

[0122] 4) Those diagnosed with eosinophilic esophagitis histologically

[0123] 5) Those with underlying lower gastrointestinal disease at screening (Visit 1) (e.g., inflammatory bowel disease (Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS))

[0124] 6) Those with warning symptoms (unintentional significant weight loss, recurrent vomiting, dysphagia, hematemesis, melena, etc.) that may be suspected of being a malignant tumor of the gastrointestinal tract at the investigator's discretion (however, those who have confirmed the presence of a tumor through an upper gastrointestinal endoscopy and have a negative result can be registered)

[0125] [Medical history and comorbidities]

[0126] 7) Those with clinically significant liver, kidney, nervous system, respiratory system, endocrine system, blood / tumor, cardiovascular system, or urinary system diseases at the time of screening (Visit 1)

[0127] 8) Those with a history of malignant tumor within 5 years of screening (Visit 1) (However, in the case of malignant tumors other than those of the digestive system, those who have been cured and have not relapsed for more than 5 years from the date of diagnosis may register)

[0128] 9) Those with clinically significant mental illness (e.g., schizophrenia, dementia, etc.)

[0129] 10) Those with a history of alcohol or drug abuse within 12 months prior to screening (Visit 1)

[0130] 11) Patients with acquired immune deficiency syndrome (AIDS) or those with a positive immune serum test result (HIV Ab)

[0131] [Medication history / treatment history]

[0132] 12) Those who have taken the following medications within the two weeks prior to screening (Visit 1) or who require continued use during the clinical trial period:

[0133] * (However, registration is possible if the selection criteria for upper gastrointestinal endoscopy are met after discontinuation during the screening period)

[0134] - Gastric acid secretion inhibitors: proton pump inhibitors (PPIs), gastric acid pump antagonists, H2 receptor antagonists, antigastrin agents, potassium-competitive acid blockers (P-CABs)

[0135] - Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

[0136] : Low doses of aspirin (less than 100 mg / day) are permitted.

[0137] : Acetaminophen - Up to 4g / day may be taken, but no more than 3 days in a 2-week period.

[0138] - Cholinergics (local administration is permitted)

[0139] - Anticholinergics

[0140] - Digestive system sedative

[0141] - Antipsychotic drugs: antipsychotics, antidepressants, antimanic drugs, anti-anxiety drugs, hallucinogens, etc.

[0142] - Adrenal cortex hormones (local administration is permitted)

[0143] - Antiplatelet and anticoagulant drugs

[0144] - Gastrointestinal motility stimulants (e.g., mosapride, metoclopramide, etc.)

[0145] - Gastric mucosal protective agents (e.g., sucralfate, rebamipide, sulglycotide, etc.)

[0146] - Antacids (e.g. aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium bicarbonate, etc.)

[0147] - Drugs metabolized by CYP2C8 (repaglinide)

[0148] - Drugs metabolized by CYP3A4 (e.g., rifampin, etc.)

[0149] *Drugs intended for pretreatment of upper gastrointestinal endoscopy, colonoscopy, and UBT (Urease Breath Test) tests (e.g., midazolam, propofol, simethicone, hyoscine butylbromide, cimetropium bromide, coolprep, magmil, pethidine, gasocol, polyethylene glycol, urea, etc.) are permitted.

[0150] **A 4-week drug-free period is required for proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs).

[0151] [Laboratory Performance Test]

[0152] 13) Those who meet the criteria below based on the results of the screening (Visit 1)

[0153] ① Serum ALT, AST, ALP, γ-GT, and total bilirubin levels are more than twice the upper limit of normal.

[0154] ② Serum creatinine and BUN levels are more than twice the upper limit of normal

[0155] ③ Positive immune serum test results (HBs Ag, HCV Ab, HIV Ab. However, registration is possible even if HCV Ab(+) is detected after treatment if HCV RNA(-) is detected)

[0156] [etc]

[0157] 14) Those who cannot undergo upper gastrointestinal endoscopy during screening (Visit 1) and clinical trial period

[0158] 15) Those who have a history of hypersensitivity to clinical trial drugs, components of Esomeprazole, benzimidazoles, penicillin antibiotics, and macrolide antibiotics.

[0159] 16) Pregnant women, breastfeeding women, or women who tested positive in a pregnancy test during screening (Visit 1)

[0160] 17) Participants in other clinical trials under development other than this clinical trial at the time of screening (Visit 1) (registration is possible if the clinical trial drug was not administered or if the participant participated in a non-interventional observational study)

[0161] 18) Those who have administered / applied clinical trial drugs or clinical trial medical devices from other clinical trials within 4 weeks of the screening (Visit 1) standard.

[0162] 19) Those who are judged unsuitable for participation in this clinical trial based on the judgment of other investigators.

[0163] Example 3-3. Validity Evaluation

[0164] Primary efficacy assessment

[0165] The primary efficacy evaluation was conducted using the proportion of subjects whose mucosal defects completely improved (CR, no mucosal defects observed in upper gastrointestinal endoscopy) by 8 weeks after administration of the clinical trial drug as the evaluation variable.

[0166] Specifically, upper gastrointestinal endoscopy was performed at Screening (Visit 1), Visit 2, Visit 4, and Visit 5, after fasting for at least 8 hours. Test results from the same institution within 2 weeks of the Screening (Visit 1) standard could be substituted. If the patient was taking medications that could affect the gastric mucosa at the time of Screening (Visit 1), an upper gastrointestinal endoscopy was performed after a 2-week drug-free period. However, in the case of PPIs and P-CABs, a 4-week drug-free period was required.

[0167] Complete recovery (CR) was defined as no mucosal defects observed in upper gastrointestinal endoscopy, and efficacy was assessed through the proportion of subjects evaluated as complete recovery (CR) based on upper gastrointestinal endoscopy results. Endoscopic interpretation results were archived, noting the areas where mucosal defects were confirmed. Endoscopic interpretation evaluations were performed by the principal investigator and an experienced internist delegated by the principal investigator, and the results of the evaluation were recorded as supporting documentation.

[0168] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0169] Secondary validity assessment

[0170] Secondary validity evaluation was conducted using the following items as evaluation variables.

[0171] 1) Proportion of subjects with complete remission (CR) of mucosal defects 4 weeks after administration of the clinical trial drug

[0172] The secondary efficacy assessment assessed the proportion of subjects with complete resolution (CR) of mucosal defects at 4 weeks after administration of the investigational drug. Specifically, complete resolution (CR) was defined as no mucosal defects observed during upper gastrointestinal endoscopy, and upper gastrointestinal endoscopy was performed in the same manner as described in the primary efficacy assessment.

[0173] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0174] 2) Changes in frequency and severity of each main symptom in the Reflux Disease Questionnaire (RDQ) at 4 and 8 weeks after administration of the clinical trial drug compared to baseline

[0175] In addition, the secondary efficacy evaluation was conducted by evaluating the frequency and severity of each symptom in the Reflux Disease Questionnaire (RDQ) at 4 and 8 weeks after administration of the investigational drug compared to the baseline. Specifically, the RDQ was conducted at screening (Visit 1), Visit 2, Visit 4, and Visit 5, and the RDQ was used to assess the eligibility of the subjects based on the results at Visit 2. However, if the test results are available within 7 days of Visit 2, they can be substituted. At each visit, the subjects filled out the RDQ questionnaire about each symptom they had experienced over the past 7 days, and the investigator used this to evaluate and collect the symptoms. The evaluation categories and scales are as follows.

[0176]

[0177] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0178] 3) Change in total score of quality of life assessment (GERD-HRQL) at 4 and 8 weeks after administration of clinical trial drug compared to baseline

[0179] Additionally, secondary efficacy assessments assessed the change in the total score of the GERD-Health-Related Quality of Life (GERD-HRQL) at 4 and 8 weeks after administration of the investigational drug compared to baseline. Specifically, the GERD-HRQL quality of life assessment was conducted at Visit 2, Visit 4, and Visit 5. Subjects completed the GERD-HRQL questionnaire themselves, and the investigator verified and collected the completed data.

[0180]

[0181] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0182] 4) Symptom changes evaluated in the subject's diary after administration of the clinical trial drug

[0183] Additionally, the secondary efficacy evaluation evaluated the symptom changes in the subjects' diaries after administration of the clinical trial drug.

[0184] - Time to first complete disappearance of major symptoms of gastroesophageal reflux disease within the first 7 days and proportion of subjects

[0185] - Percentage of days without major symptoms of GERD during the first 7 days [daytime, nighttime, all day]

[0186] - Proportion of subjects with complete resolution of major symptoms of GERD by 4 and 8 weeks

[0187] - Percentage of days without major GERD symptoms during weeks 4 and 8 [daytime, nighttime, all day]

[0188] - Symptom assessment within the first 24 hours

[0189] - Symptom assessment for the first 7 days

[0190] Specifically, the subject diaries were distributed to the subjects at Visits 2 and 4 and collected at each subsequent visit. Subjects completed the diaries on their own from the day of administration of the clinical trial drug. The scale for assessing daytime / nighttime heartburn and acid reflux symptoms (0–4 points) was as follows:

[0191]

[0192] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0193] Exploratory Validity Assessment Variables

[0194] Exploratory validity evaluation was conducted using the following items as evaluation variables.

[0195] 1) The proportion of subjects with complete remission (CR) of mucosal defects according to the following subcategories at 4 and 8 weeks after administration of the clinical trial drug.

[0196] - LA classification

[0197] - H. pylori infection

[0198] H. pylori testing was performed only once, at screening (Visit 1) or Visit 2, and was performed by either the UBT (Urease Breath Test), CLO (Campylobacter-like organism), or tissue biopsy. For the UBT test, fasting was maintained for a certain period of time according to the urea approval, and if there was a history of antibiotics, PPIs, or bismuth preparations (e.g., pepto bismol) administration within 4 weeks of the test date, the test was performed after discontinuation.

[0199] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0200] 2) Changes in blood gastrin concentration at 4 and 8 weeks after administration of the clinical trial drug compared to baseline

[0201] Blood gastrin concentration tests were evaluated through analysis results from the central laboratory at Visit 2, Visit 4, and Visit 5.

[0202] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0203] 3) Changes in blood Pepsinogen I / II concentrations at 4 and 8 weeks after administration of the clinical trial drug compared to baseline

[0204] Blood Pepsinogen I / II concentration tests were evaluated through analysis results from the central laboratory at Visit 2, Visit 4, and Visit 5.

[0205] It is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to a degree indicating therapeutic efficacy through the above experiment.

[0206] The results of the efficacy evaluation of Example 3-3 are expected to be significant or remarkably effective in the treatment of erosive gastroesophageal reflux disease. Specifically, in the upper gastrointestinal endoscopy, reflux disease symptom evaluation (RDQ), quality of life evaluation (GERD-HRQL), symptom evaluation in the subject diary, H. pylori test, blood Gastrin concentration test, blood Pepsinogen I / II concentration test, etc. of Example 3-3, it is expected that the symptoms of experimental groups 1 and 2 administered with the compound of chemical formula 1 of the present invention will be significantly reduced to indicate therapeutic efficacy.

[0207] Moreover, the therapeutic agent according to the present invention has high therapeutic value as an appropriate dosage range for the target disease, as more than 85% of patients show therapeutic efficacy within at least 2, 3, or 4 weeks of drug administration.

[0208] Example 3-4. Safety Evaluation

[0209] Safety endpoints were assessed through collected adverse events, laboratory tests (hematology, blood chemistry, coagulation, and urinalysis), vital signs, physical examinations, and electrocardiograms. Results were recorded in an eCRF, and laboratory tests were performed at each study site.

[0210] It is expected that sufficient safety will be shown in experimental groups 1 and 2 administered the compound of chemical formula 1 of the present invention through the above experiment.

Claims

1. A pharmaceutical composition for preventing or treating gastrointestinal diseases, which comprises administering a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof in a total of 10 mg to 80 mg once or twice a day: [Chemical Formula 1] .

2. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is fumaric acid.

3. A pharmaceutical composition according to claim 1, wherein the composition is for oral administration.

4. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day.

5. A pharmaceutical composition according to claim 1, wherein the composition is administered once a day in an amount of 20 to 40 mg.

6. A pharmaceutical composition according to claim 5, wherein the composition is administered once a day at 40 mg.

7. A pharmaceutical composition according to claim 5, wherein the composition is administered once a day at 20 mg.

8. A pharmaceutical composition according to claim 5, wherein the composition is administered once a day before a meal.

9. A pharmaceutical composition according to claim 5, wherein the composition is administered once a day for 1 to 8 weeks.

10. A pharmaceutical composition according to claim 9, wherein the composition is administered once a day for 4 to 8 weeks.

11. A pharmaceutical composition according to claim 9, wherein the composition is administered once a day at a dose of 20 to 40 mg for 4 to 8 weeks.

12. A pharmaceutical composition according to claim 1, wherein the gastrointestinal disease is erosive esophagitis or reflux esophagitis.

13. A pharmaceutical composition according to claim 12, wherein the gastrointestinal disease is erosive esophagitis.

14. A method for preventing or treating a gastrointestinal disease, comprising administering to a subject in need of prevention or treatment of a gastrointestinal disease a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, once or twice a day, in a total of 10 mg to 80 mg: [Chemical Formula 1] .

15. A composition for use in the prevention or treatment of gastrointestinal diseases by administering a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof in a total amount of 10 mg to 80 mg once or twice a day: [Chemical Formula 1] . 16.1 Use of a composition comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for preventing or treating gastrointestinal diseases by administering a total of 10 mg to 80 mg once or twice a day: [Chemical Formula 1] .

Images