Pharmaceutical composition for preventing or treating functional dyspepsia

Abstract

The present invention relates to a pharmaceutical composition comprising mosapride or nortriptyline for preventing or treating functional dyspepsia.

Description

Pharmaceutical composition for the prevention or treatment of functional dyspepsia

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of functional dyspepsia.

[0002] The present invention relates to a pharmaceutical composition for the prevention or treatment of functional dyspepsia. Functional dyspepsia includes symptoms such as upper abdominal discomfort, pain, postprandial fullness, and early satiety, which can significantly affect daily life. Currently, various drugs are used to treat functional dyspepsia, but an effective treatment method has not yet been established.

[0003]

[0004] The present invention aims to provide a pharmaceutical composition for functional dyspepsia.

[0005]

[0006] 1. A pharmaceutical composition for the prevention or treatment of functional dyspepsia comprising mosapride or nortriptyline.

[0007] 2. In the above 1, the mosapride is a sustained-release formulation, a pharmaceutical composition for the prevention or treatment of functional dyspepsia.

[0008] 3. A pharmaceutical composition for the prevention or treatment of functional dyspepsia that improves indigestion, anxiety, or depression, in accordance with 1 above.

[0009]

[0010] The pharmaceutical composition of the present invention can exhibit excellent pharmacological effects for functional dyspepsia.

[0011] The pharmaceutical composition of the present invention can improve various symptoms such as indigestion, anxiety, and depression.

[0012]

[0013] Fig. 1. Schematic diagram of the study flow. ITT, treatment intent; MITT, modified treatment intent; PP, by protocol.

[0014] Fig. 2. Proportion of patients with improved overall dyspepsia after a 4-week trial. (A) Modified Intent to Treat (MITT) analysis set. (B) Protocol-specific (PP) analysis set.

[0015] Fig. 3. Proportion of patients with improved overall dyspepsia after a 4-week trial according to functional dyspepsia subtypes. (A) Modified treatment intent MITT analysis set. (B) Protocol-specific (PP) analysis set. PDS, postprandial pain syndrome; EPS, epigastric pain syndrome.

[0016]

[0017] The present invention will be described in detail below.

[0018]

[0019] The present invention relates to a pharmaceutical composition for the prevention or treatment of functional dyspepsia.

[0020] The pharmaceutical composition of the present invention comprises mosapride or nortriptyline.

[0021] Mosapride is a gastroprokinetic agent primarily used to treat digestive disorders such as functional dyspepsia and gastroesophageal reflux disease. Mosapride activates serotonin receptors (5-HT4 receptors) to promote gastrointestinal motility, facilitate gastric emptying, and increase gastrointestinal motility. Through this mechanism, it can alleviate symptoms such as indigestion, heartburn, and nausea.

[0022] Mosapride can be, for example, a controlled-release formulation.

[0023] Nortriptyline is a tricyclic antidepressant (TCA) primarily used to treat depression. Nortriptyline blocks the reabsorption of the neurotransmitters serotonin and norepinephrine, thereby increasing their concentrations and improving mood and alleviating symptoms of depression.

[0024] Functional dyspepsia (FD) refers to a digestive disorder caused by functional problems in the gastrointestinal tract. This condition is characterized by chronic indigestion accompanied by upper abdominal discomfort or pain without organic lesions. Functional dyspepsia is common worldwide and causes a variety of digestive symptoms.

[0025] The main symptoms of functional dyspepsia include upper abdominal pain, upper abdominal burning, early satiety, postprandial discomfort, bloating, and nausea. These symptoms cause significant inconvenience in daily life and reduce the patient's quality of life.

[0026] The pharmaceutical composition of the present invention exhibits excellent pharmacological effects for functional dyspepsia. For example, it can improve indigestion, anxiety, or depression.

[0027] The time of administration of the pharmaceutical composition of the present invention is not particularly limited. For example, if the pharmaceutical composition of the present invention contains mosapride, it may be taken before breakfast, and if it contains nortriptyline, it may be taken before bedtime.

[0028] The pharmaceutical composition of the present invention is not limited to these but may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, as well as topical preparations, suppositories, and sterile injectable solutions, according to conventional methods. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. For oral administration, the pharmaceutically acceptable carrier may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. For injectable preparations, it may include buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc., in combination; and for topical administration, a base, excipients, lubricants, preservatives, etc. may be used. The formulations of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injectables, it can be manufactured in the form of unit dosing ampoules or multiple dosing ampoules. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release formulation, etc.

[0029] Examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Additionally, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

[0030] The routes of administration of the pharmaceutical composition of the present invention are not limited to but include oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local, sublingual, or rectal. Oral or parenteral administration is preferred. The parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques.

[0031] The pharmaceutical composition of the present invention may vary depending on various factors including age, body weight, general health, gender, diet, time of administration, route of administration, release rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art, depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and duration, and may be administered at a dose of 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several doses. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, coated tablet, capsule, liquid, gel, syrup, slurry, or suspension.

[0032]

[0033] The present invention will be explained in more detail below with reference to examples.

[0034]

[0035] Examples

[0036] Materials and Methods

[0037] Research Design Overview

[0038] A multi-center, double-placebo, double-blind, randomized controlled, parallel clinical study was conducted at 15 hospitals in Korea. Ethical approval regarding the scientific and ethical aspects of the Korean study was obtained from the ethics committees of each institution prior to the start of the study. (Daegu Catholic University Medical Center [CR-19-094-L], Eunpyeong St. Mary's Hospital [PC19MEDV0053], Gangneung Asan Medical Center [GNAH 2019-06-022], Dankook University Hospital [DKUH 2019-07-004], Konyang University Hospital [KYUH 2019-07-006], Keimyung University Hospital [DSMC 2019-07-022], Ewha Womans University Hospital Seoul [SEUMC 2019-06-019], Seoul National University Bundang Hospital [B-1908 / 558-007], Inje University Ilsan Paik Hospital [ISPAIK 2019-07-002], Gangnam Severance Hospital [3-2019-0177], Incheon St. Mary's Hospital [OC-19MEDV0100], Gyeongsang National University Written informed consent was obtained from all patients at Changwon St. Mary's Hospital [GNUCH 2019-06-035] and Bucheon St. Mary's Hospital [HC20MIDV0068]. All study procedures complied with the Helsinki Declaration on the Protection of Human Participants and adhered to Good Clinical Practice guidelines. This study was registered on the Korea Clinical Research Information Service (http: / cris.nih.go.kr) on October 8, 2019, under identification number KCT0004340.

[0039]

[0040] Patient Information

[0041] Study participants were patients aged 19 years or older diagnosed with FD according to the Rome IV criteria. These symptoms were severe enough to interfere with general activities, began at least 6 months prior, and occurred at least 3 days per week during the past 3 months. No structural lesions were found in the upper gastrointestinal tract on endoscopy 12 weeks prior to enrollment. Potential participants were excluded if they had hypersensitivity or allergy to the study drug, were taking other medications that could alter gastrointestinal motility, had undergone abdominal surgery that could alter gastrointestinal motility (excluding appendectomy and hysterectomy), or had peptic ulcer, gastric cancer, esophageal cancer, acute or chronic pancreatitis, pancreatic cancer, inflammatory bowel disease, biliary disease (excluding asymptomatic cholelithiasis), diabetic gastroparesis, major symptoms of gastroesophageal reflux, or irritable bowel syndrome other than dyspepsia. Recent history of taking medications affecting the gastrointestinal tract: prokinzetics, erythromycin, acid secretion inhibitors (histamine 2 receptor antagonists, PPIs, or potassium-competitive acid blockers), gastric mucoprotectives, anticholinergics, antispasmodics, antidepressants (tricyclic antidepressants and selective 5-HT reuptake inhibitors), systemic nonsteroidal anti-inflammatory drugs, and systemic glucocorticoids. Patients wishing to participate in the study could be enrolled after a one-week washout period.

[0042]

[0043] Research Design

[0044] Participants were randomized in a 1:1 ratio to either the mosapride extended-release (CR) mosapride group or the nortriptyline group using a block randomization method. Patients were assigned to treatment according to a sequentially numbered randomization list in the order in which calls were received. Study staff, participants, and data analysts were unaware of the assignments until the study was completed. Hospital pharmacists packaged the medications in identical containers according to the randomization codes.

[0045] In the mosapride CR group, mosapride CR (15 mg) (Gastiin CR, Korea United Pharm, Inc, Seoul, South Korea), a medication providing immediate sustained drug release that can be taken once daily, was administered before breakfast, and nortriptyline placebo, which has no active ingredient, was administered before bedtime. It was packaged identically to nortriptyline (10 mg) in appearance, packaging, storage method, and dosage, and was administered for 4 weeks. In the nortriptyline group, mosapride CR placebo, which has no active ingredient, was administered before breakfast, and nortriptyline (10 mg; Sensival tab, Ilsung Pharm Co, Seoul, South Korea) was administered before bedtime for 4 weeks. During the treatment period, magnesium oxide was permitted as a rescue medication at a dose of 250 mg, up to 3 times daily, and the amount of rescue medication taken was documented.

[0046] Blood analysis (including total blood cell count, electrolytes, liver function tests, blood urea nitrogen, creatinine, glycated hemoglobin, and H. pylori immunoglobulin G), urinalysis (including human chorionic gonadotropin) and electrocardiogram were performed before the test and during the 4 weeks of the test.

[0047]

[0048] Result measurement

[0049] The primary evaluation variable was defined as the rate of improvement in overall dyspepsia. This was assessed using a 7-point Likert scale (significantly worsened, worsened, slightly worsened, no change, slightly improved, greatly improved, very greatly improved) after 4 weeks of treatment. Improvement in overall dyspepsia was defined as responding "greatly improved" or "very greatly improved" after 4 weeks of drug administration.

[0050] Secondary evaluation variables included (1) changes in the frequency and severity of gastrointestinal symptoms determined using the self-assessed dyspepsia questionnaire (SEQ-DYSPEPSIA), (2) changes in anxiety and depression determined using the Hospital Anxiety and Depression Scale (HADS), and (3) changes in quality of life (QoL) determined using the Napean Dyspepsia Index-Korean Version (NDI-K) questionnaire, and were evaluated 4 weeks after the start of treatment. In addition, the number of rescue medication uses and adverse reactions were calculated.

[0051] SEQ-DYSPEPSIA is a 5-point Likert scale consisting of 11 items, including major FD symptoms (epigastric pain, epigastric burning, postprandial satiety, early satiety) and secondary symptoms (abdominal bloating, belching, nausea). It has been reported to have good internal consistency (alpha = 0.770–0.905) and acceptable test-retest reliability (intra-class correlation coefficient = 0.733–0.859). HADS is a frequently used tool for assessing psychological distress, consisting of 7 items for the anxiety subscale and 7 items for the depression subscale. The internal consistency of the Korean version of HADS was reported as 0.89 for anxiety and 0.86 for depression. NDI-K consists of 25 questions across 5 QoL domains: stress / sleep, disturbance in daily life, eating / drinking, knowledge and control, and work / study. Questions are scored on a scale of 1 to 5, with higher scores indicating better QoL.

[0052] Adverse reactions were defined as any undesirable medical symptom or condition (including changes in laboratory values) that occurred in a participant during the administration of the test drug, regardless of an apparent causal relationship. The amount of magnesium oxide used as a rescue drug during the treatment period was calculated.

[0053]

[0054] Sample size

[0055] Sample size estimation was based on detecting the proportion of patients who showed overall dyspeptic improvement after the trial. Previous studies reported a proportion of mosapride CR of 56.9% and nortriptyline CR of 53.6%. The sample estimate used an error margin of 2.3% to estimate the actual value of the proportion of total dyspeptic responders to be approximately 4.5%. Assuming an alpha value of 0.05, a desired power of 80%, and a dropout rate of 20%, a minimum of 108 participants had to be recruited, with 54 participants from each group.

[0056]

[0057] Statistical methods

[0058] Baseline participant characteristics between the mosapride CR group and the nortriptyline group were compared using Pearson's chi-square test or Fisher's exact test for categorical variables and independent sample t-tests for continuous variables. The proportion of patients with overall dyspeptic improvement was compared in the modified intentional treatment (MITT) and protocol adherence (PP) analysis sets between the two groups and according to the FD subtypes of the two groups. Changes in the frequency and severity of gastrointestinal symptoms, anxiety and depression, and QoL 4 weeks after baseline were compared using two-sample or Mann-Whitney U tests. The frequency of adverse events and the number of rescue medication uses in the mosapride CR group and the nortriptyline group were compared using independent sample t-tests. Statistical analysis was performed using SPSS version 21 for Windows (IBM Corp, Armonk, New York, USA). Data were expressed as mean ± standard deviation (SD). A two-sided P-value < 0.05 was considered statistically significant.

[0059]

[0060] result

[0061] Research participants

[0062] The screening and recruitment flow of study participants is shown in Figure 1. From August 2019 to June 2021, 109 potential participants were recruited and evaluated for eligibility, and 107 participants were randomly assigned to the mosapride CR group (n = 54) and the nortriptyline group (n = 53). Three participants in the nortriptyline group were excluded because they declined participation (n = 2) or missed follow-up (n = 1). 54 participants from the mosapride CR group and 50 from the nortriptyline group were included in the MITT analysis. Fifteen participants, including 8 from the mosapride CR group and 7 from the nortriptyline group, completed outcome measurements via questionnaires even though they did not take the study drug for at least 80% of the time or took prohibited drugs. These participants were excluded from the PP analysis but included in the MITT analysis. There were no significant differences in baseline clinical characteristics between the two groups (Table 1).

[0063]

[0064]

[0065]

[0066] Criteria clinical characteristics of study participants: CR, controlled release, FD, functional dyspepsia, PDS, postprandial pain syndrome, EPS, epigastric pain syndrome. Data are expressed as mean ± SD or n(%).

[0067]

[0068] Key evaluation variables

[0069] The primary endpoint of this study was the rate of improvement in overall dyspepsia, defined as the proportion of participants who answered "significantly improved" or "very significantly improved" regarding overall dyspepsia after a 4-week trial. After 4 weeks of drug administration, the proportion of total responders was 53.7% (29 / 54) in the mosapride CR group and 54.0% (27 / 50) in the nortriptyline group (P = 0.976) (MITT analysis set). In the PP analysis set as well, there was no difference in the rate of improvement in overall dyspepsia between the mosapride CR group (54.4%) and the nortriptyline group (55.8%) (P = 0.890) (Fig. 2). Furthermore, according to the FD subtype, the rate of improvement in overall dyspepsia after 4 weeks of drug administration was similar in both the MITT and PP analysis sets, regardless of the specific treatment group such as mosapride CR or nortriptyline (Fig. 3).

[0070]

[0071] Secondary efficacy evaluation criteria

[0072] Changes in the overall symptoms of functional dyspepsia

[0073] Regarding changes in the overall frequency and severity of symptoms after 4 weeks of drug administration, significant symptom improvement was observed in both the mosapride CR group and the nortriptyline group. Additionally, there was no difference in the degree of improvement between the mosapride CR group and the nortriptyline group. In the subgroup analysis of individual symptom relief scores 4 weeks after drug administration, all symptoms except vomiting were found to have improved in both the MITT (Table 2) and PP (Table 3) analysis sets.

[0074]

[0075]

[0076]

[0077] Changes in total symptoms and individual symptom relief scores following 4 weeks of drug administration

[0078] CR, controlled emission. Data are expressed as mean ± SD.

[0079]

[0080]

[0081]

[0082] Changes in total symptoms and individual symptom relief scores following 4 weeks of drug administration

[0083] Data is displayed as mean ± SD.

[0084]

[0085] Anxiety, depression, quality of life

[0086] After 4 weeks of drug administration, anxiety and depression improved in both groups. The degree of improvement did not show a significant difference between the mosapride CR group and the nortriptyline group in the MITT (Table 4) and PP (Table 5) analysis sets.

[0087] Regarding quality of life (QoL) after 4 weeks of drug administration, significant improvement was observed in both the mosapride CR group and the nortriptyline group. The improvement in QoL was greater in the nortriptyline group than in the mosapride CR group (17.2 ± 19.2 in the mosapride CR group, 24.9 ± 22.8 in the nortriptyline group, P= 0.023).

[0088]

[0089]

[0090]

[0091] Changes in anxiety, depression, and quality of life after 4 weeks of medication

[0092] CR, controlled emission. Data are expressed as mean ± SD.

[0093]

[0094]

[0095]

[0096] Changes in anxiety, depression, and quality of life after 4 weeks of medication

[0097] Data is displayed as mean ± SD.

[0098]

[0099] Use and Safety of Rescue Drugs

[0100] There was no difference in the average number of rescue tablets used between the two groups (0.5 ± 1.1 in the mosapride CR group and 1.0 ± 2.1 in the nortriptyline group, P = 0.380). Additionally, no serious adverse events were reported. As shown in Table 6, mild adverse events were reported in 14.3% (8 / 54) of patients in the mosapride CR group and 12.0% (6 / 50) of patients in the nortriptyline group. All adverse events resolved after discontinuation of treatment. However, 7 patients (12.3%) in the mosapride CR group and 6 patients (14.0%) in the nortriptyline group discontinued the drug due to adverse events (P = 0.881).

[0101]

[0102]

[0103]

[0104] The types of adverse side effects include all various adverse reactions of the subjects.

[0105] CR, controlled emission. Data is indicated as n(%).

Claims

1. A pharmaceutical composition for the prevention or treatment of functional dyspepsia comprising mosapride or nortriptyline.

2. The pharmaceutical composition for the prevention or treatment of functional dyspepsia, wherein the mosapride is a sustained-release formulation according to Claim 1.

3. A pharmaceutical composition for the prevention or treatment of functional dyspepsia that improves indigestion, anxiety, or depression, in accordance with Claim 1.

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