Pharmaceutical composition containing rebamipide for use in the prevention and treatment of celiac disease

Abstract

Rebamipide is provided for use in a method for the prevention and / or treatment of celiac disease, particularly in individuals with or at risk of having increased intestinal permeability.Rebamipide is provided for use in a method for inhibiting increased intestinal permeability in gluten sensitivity.

Description

[Technical field]

[0001] The present invention relates to rebamipide for use in the prevention and / or treatment of celiac disease, particularly in individuals with or at risk of having increased intestinal permeability.Furthermore, the present invention relates to rebamipide for use in a method for inhibiting increased intestinal permeability in gluten sensitivity. [Background technology]

[0002] Celiac disease (CD), also known as gluten-sensitive enteropathy, is a multifactorial autoimmune disorder that occurs especially in genetically susceptible individuals who express the HLA-DQ2 / -DQ8 haplotype. It is caused by an intolerance to gluten, a protein that occurs naturally in grains such as wheat, rye, and barley. When people with celiac disease ingest gluten, it triggers an autoimmune inflammation of the intestinal mucosa. Over time, this reaction damages the villi (tiny finger-like projections on the lining of the small intestine) that absorb nutrients. When the villi are damaged, nutrients are not properly absorbed by the body. Intestinal damage often causes diarrhea, fatigue, weight loss, abdominal bloating, and anemia, and can lead to serious complications.

[0003] The disorder can occur at any age and is estimated to affect 1 in 100 people worldwide. In children, it often begins soon after a first exposure to gluten, but symptoms can also appear after years of uneventful gluten intake. In the latter case, the disorder may become apparent after a triggering event, such as an illness or a stressful life event such as pregnancy.

[0004] Gluten is a mixture of seed storage proteins and accounts for up to 80% of the protein in wheat seeds. Dietary gluten has numerous homologous proteins, including gliadin and glutenin in wheat, hordein in barley, and secalin in rye. All of these proteins have multiple disease-specific T cell epitopes. Gluten proteins have similar amino acid sequences and often contain repeats rich in proline and glutamine residues. Once gluten enters the digestive system, it is partially hydrolyzed by proteases present in the gastrointestinal tract. However, due to their high proline content, gluten proteins are particularly resistant to extensive proteolysis by intestinal proteases and brush border membrane enzymes of enterocytes, resulting in long fragments of undigested gluten proteins remaining in the upper part of the small intestine and potentially exposed to the inductive arm of the intestinal immune system as immunogenic peptides enabling responses by T and B cells. Elimination of these proteins from the diet results in complete remission.

[0005] The human intestine is lined with a single layer of epithelial cells bound by tight junctions, adherens junctions, and desmosomes. Peptides can cross the intestinal epithelium by either the paracellular or transcellular pathway. Under normal physiological conditions, the majority of antigens (approximately 90%) passing through the intestinal epithelium do so via the transcellular pathway. The transcellular pathway is regulated and results in antigen degradation in lysosomes into non-immunogenic peptide fragments. The remaining approximately 10% of proteins cross the epithelium via the paracellular pathway, with antigen transport tightly controlled by intestinal tight junction regulation, leading to antigen tolerance.

[0006] In healthy individuals, gluten peptides taken up into intestinal cells are almost completely degraded in the lysosomal system during transcytosis (Non-Patent Document 1), which makes it easier to avoid excessive activation of the local immune system. In contrast, in active CD, many peptides pass through the intestinal mucosa, and a significant proportion reach the lamina propria intact. The mechanism is that gluten peptides bind to secretory IgA at the apical membrane of the intestine, and then bind to the transferrin receptor CD71 on intestinal cells. These are then transported transcytically, and the gluten peptides are delivered to the lamina propria (Non-Patent Document 2).

[0007] Interestingly, gluten peptides also cross the epithelial layer via the paracellular pathway, which is involved in the degradation of intercellular tight junctions. Upon reaching the intestinal lumen, gluten peptide fragments bind to the chemokine CXC receptor 3 (CXCR3), which recruits myeloid differentiation factor 88 (MyD88), resulting in the release of zonulin into the lumen (Non-Patent Document 3). Zonulin is the only reported physiological regulator of intercellular tight junctions, and binds to epidermal growth factor receptor (EGFR) and protease-activated receptor 2 (PAR2) in the intestinal epithelium. This complex initiates a signaling pathway that leads to phosphorylation of tight junction proteins, causing the degradation of small intestinal tight junctions and increasing intestinal permeability to macromolecules, resulting in the leakage of gluten peptides from paracellular membranes.

[0008] Like many other autoimmune diseases, CD involves innate and adaptive immune responses. First, gluten peptides enter the lamina propria by the mechanism described above. Here, gluten peptides can activate both dendritic cells and macrophages to produce interleukin 15 (IL-15), which then upregulates the expression of stress proteins MICA / B and HLA-E in enterocytes. These proteins are recognized by the natural killer receptors NKG2D and NKG2C present on intraepithelial lymphocytes (IELs), whose expression is also upregulated by IL-15 (Non-Patent Documents 4, 5). This process triggers the cytotoxic and apoptotic activity of IELs, as well as epithelial cell injury, via the perforin / granzyme pathway and / or the Fas / FasL pathway (Non-Patent Document 6).

[0009] The adaptive immune response involves the binding of gluten peptides present in the intestinal lamina propria to antigen-presenting cells (APCs), particularly dendritic cells. These cells present gluten peptides to T cell receptors, which strongly activate CD4+ T cells that can induce B lymphocyte differentiation into plasma cells that produce specific antibodies against gluten. Furthermore, gluten peptides are deamidated by tissue transglutaminase (tTG or TG2), which increases their affinity for MHC II molecules such as HLA-DQ2 or DQ8 presented by APCs. This deamidation process allows APCs to take up not only immunogenic peptides but also tTG-peptide complexes. As a result, antibodies are produced not only against gluten peptides but also against tTG (Non-Patent Document 7). CD4+ T cells also secrete inflammatory cytokines, mainly interferon (IFN) gamma. Inflammatory cytokines stimulate cytotoxic T cells and fibroblasts to produce matrix metalloproteinases (MMPs), which are responsible for the degradation of both the extracellular matrix and the basement membrane.

[0010] The inflammatory process described above destroys the structure and function of the mucosal lining of the small intestine, resulting in flattening of the villi and hyperplasia of the crypts. Currently, the only known effective treatment for celiac disease is a strict lifelong gluten-free diet. In the majority of patients, this diet restores the intestinal mucosa, improves symptoms, and reduces the risk of developing complications. If left untreated, it can lead to cancers, such as intestinal lymphoma. Therefore, alternative therapies are increasingly needed.

[0011] Rebamipide (chemical name: 2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinolin-4-yl)propanoic acid) is used to treat acute and / or chronic gastritis and gastroduodenal ulcers. Its mechanism of action involves mucosal defense, free radical scavenging, and transient activation of the gene encoding cyclooxygenase-2. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Matysiak-Budnik T, Candalh C, Dugave C, Namane A, Cellier C, Cerf-Bensussan N, Heyman M: Alterations of the intestinal transport and processing of gliadin peptides in celiac disease. Gastroenterology 2003;125:696-707 [Non-Patent Document 2] Matysiak-Budnik T et al.Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease.J Exp Med.2008;205(1):143-54 [Non-Patent Document 3] Lammers KM et al.Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3,Gastroenterology 2008;135(1):194-204

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[0013] It has been unexpectedly found that administration of rebamipide to patients with celiac disease can suppress disease symptoms and even lead to complete remission. This is quite surprising, since rebamipide, which is clinically used to treat gastrointestinal disorders, has not been reported to be effective in celiac disease, which mainly affects the small intestine. Although rebamipide has been on the market since 1990, little is known about its behavior in the intestinal tract. Since this molecule is poorly absorbed in the digestive tract, oral administration would likely reach the intestinal mucosa in sufficient concentrations to exert a therapeutic effect. In this light, it is presumed that the mechanism of action of rebamipide in celiac disease is probably based on its ability to promote mucin production in the intestine, suppress inflammation, and even reduce the permeability of the intestinal wall. [Means for solving the problem]

[0014] The present invention therefore provides rebamipide or a pharmaceutical composition thereof for use in a method for the prevention and / or treatment of celiac disease, in particular by reducing intestinal permeability.Preferably, rebamipide is used for the prevention and / or treatment of celiac disease in individuals adhering to a gluten-free diet.

[0015] As used herein, "rebamipide" is intended to include any form of this active ingredient, such as anhydrous, hydrated, or solvated (e.g., hemihydrate), crystalline form, and pharma- ceutically acceptable salts thereof.

[0016] "Prevention" or "prophylactic use" is understood herein to mean preventing or delaying the onset of celiac disease, including, for example, the recurrence of symptoms in patients who have been in complete or partial remission following a gluten-free diet or other previous treatments, and also includes preventing the worsening of disease symptoms following gluten ingestion in individuals adhering to a gluten-free diet.

[0017] "Treatment" is herein understood as a therapy that can inhibit, prevent, delay or reverse the progression of celiac disease, and includes suppression of chronic inflammation of the small intestine, reduction of villous atrophy and / or crypt hyperplasia, reduction of abnormal intestinal permeability, and gradual disappearance of autoantibodies.It is also intended to include improvement or alleviation of clinical symptoms of the disease, such as diarrhea, abdominal bloating, fatigue, abdominal pain, nausea and vomiting, constipation, weight loss, oral ulcers, iron deficiency anemia, depression or anxiety, dermatitis herpetiformis, headache, bone mineral density loss, arthritis, etc.

[0018] As used herein, "gluten" is intended to include proteins present in wheat or related cereal species, including barley, rye, or oats, that may be harmful to certain humans. The gluten proteins specifically include alpha, beta, gamma, and omega glutenins, and low and high molecular weight (LMW and HMW) glutenins in wheat, B, C, and D hordeins in barley, beta, gamma, and omega secalins in rye, and avenins in oats.

[0019] The current body of evidence suggests that the development of celiac disease involves multiple factors, including genetic predisposition and environmental factors. Increased intestinal permeability is suggested to be another important factor in the development of celiac disease, as it allows gluten peptides to enter the lamina propria, where gluten-reactive T cells reside. Studies with Irish Setter dogs, a naturally occurring model of gluten sensitivity, have shown that increased intestinal permeability can be present even before the onset of this autoimmune disease (Non-Patent Document 8). In the framework of the present invention, it was surprisingly found that rebamipide also helps to normalize intestinal permeability in patients with celiac disease. This is likely due to rebamipide's ability to restore tight junction function in epithelial cells, thereby reducing the permeability of the intestinal wall and inhibiting the entry of gluten into the lamina propria. This contributes to the suppression of chronic inflammation and to prevent further tissue damage due to the autoimmune reaction.

[0020] In one aspect, the present invention provides rebamipide for use in a method for the prevention and / or treatment of celiac disease in individuals with or at risk of having increased intestinal permeability, for example because of a family history of the condition or because of exposure to conditions or substances that induce increased intestinal permeability. In a preferred embodiment, rebamipide is used in a method for the prevention of celiac disease.

[0021] The term "increased intestinal permeability" as used herein refers to subtle intestinal wall defects, such as those resulting from subclinical chronic inflammation (low-grade inflammation) of the intestinal wall. Such intestinal wall defects may present with other medical conditions, such as celiac disease, chronic constipation, and gastroparesis. Intestinal permeability may be diagnosed using specific tests, such as the lactulose-mannitol test (La / Ma test, e.g., Non-Patent Document 9), the A-1-AT test, or the zonulin test. In general, intestinal permeability refers to the permeability of the intestinal wall to particles with a radius larger than 4 angstroms.

[0022] Substances that induce increased intestinal permeability include nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, diclofenac, ketorolac, etodolac, indomethacin, tolmetin, piroxicam, meloxicam, and selective COX-2 inhibitors, such as celecoxib and etoricoxib, alcohol, nicotine, food additives, antibiotics, and chemotherapy drugs.Therefore, simultaneous or sequential co-administration of rebamipide with nonsteroidal anti-inflammatory drugs, chemotherapy drugs, or antibiotics prevents intestinal wall damage, thereby preventing or delaying the onset of celiac disease associated with increased intestinal permeability.Prophylactic use of rebamipide may also be beneficial for people who abuse alcohol, nicotine, or other drugs known to damage the intestinal wall. The term "abusing" as used herein is meant to include any consumption that is not necessary for medical reasons and that leads to a state of dependency and / or health problems such as mild inflammation of the intestinal wall.

[0023] Conditions such as increased intestinal permeability are related to stress, unbalanced diet, allergies, bacterial, viral or parasitic infections and various drug treatments, such as stress gastritis, food poisoning, cholic acid imbalance, gastric HCl and pepsin secretion, non-infectious diarrhea, radiation therapy, chemotherapy, infectious or post-infectious disorders of the GIT mucosa, and dysmicrobia (e.g. induced by antibiotic therapy).

[0024] A person with increased intestinal permeability usually has at least one condition selected from low-grade inflammation of the intestinal wall, chronic constipation, or gastroparesis.

[0025] In one aspect, the present invention provides a method for preventing and / or treating celiac disease by administering a pharma- ceutical effective amount of rebamipide or a pharmaceutical composition thereof to a subject in need of such treatment.The subject is preferably a human subject, particularly a person with or at risk of having increased intestinal permeability.Furthermore, the present invention also includes the use of rebamipide in the manufacture of a medicament for preventing and / or treating celiac disease, particularly in a person with or at risk of having increased intestinal permeability.

[0026] In one aspect, the present invention provides rebamipide for use in a method for suppressing increased intestinal permeability due to gluten sensitivity, the method comprising administering to a subject in need thereof an amount of rebamipide or a composition thereof sufficient to suppress said increased intestinal permeability.The present invention further includes the use of rebamipide in the manufacture of a composition for suppressing increased intestinal permeability due to gluten sensitivity.

[0027] In the therapeutic applications described in the present invention, rebamipide may be preferably used in oral dosage forms such as tablets, capsules, sugar-coated tablets, granules, microgranules (sachets), orodispersible tablets or films, sublingual tablets, crushed tablets, oral liquids, oral suspensions, syrups, mouthwashes, or mouthwashes. Alternatively, it may be used in rectal dosage forms such as suppositories and enemas. Preferably, the oral dosage forms such as tablets, capsules, sugar-coated tablets, and granules are in enteric release form, such as enteric sustained release or enteric controlled release.

[0028] The dosage form may include at least one pharma- ceutically acceptable excipient selected from fillers, binders, lubricants, flow agents, disintegrants / swelling agents, solubilizers, enteric release agents, mucoadhesive components, sustained release agents, preservatives, coatings, and colorants. Such excipients are known in the art of pharmaceutical formulations, and the skilled artisan can select an excipient suitable for the relevant dosage form.

[0029] Suitable methods of preparing the dosage forms and compositions include wet or dry granulating the active ingredient with the auxiliary substances and ingredients, or directly homogenizing the active ingredient with the auxiliary substances and ingredients.

[0030] The filler may preferably be selected from sugar alcohols (such as mannitol, sorbitol, xylitol), lactose, starch, pregelatinized starch, cellulose, silicified cellulose, calcium hydrogen phosphate, calcium phosphate, sucrose, and calcium sulfate. The filler may preferably be present in an amount of 5 to 90% by weight relative to the total weight of the composition.

[0031] The binder may preferably be selected from starch, pregelatinized starch, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, cellulose. The binder may preferably be present in an amount of 1-20% by weight relative to the total weight of the composition.

[0032] The lubricant may preferably be chosen from magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, and sodium stearyl fumarate. The lubricant may preferably be present in an amount of up to 5% by weight relative to the total weight of the composition.

[0033] The flow agent may preferably be chosen from silica, talc and sodium lauryl sulfate. The flow agent may preferably be present in an amount ranging from 0.5 to 10% by weight relative to the total weight of the composition.

[0034] The disintegrant and / or swelling agent may preferably be selected from crospovidone, copovidone, povidone, croscarmellose, hydroxypropylmethylcellulose, starch, pregelatinized starch, low-substituted hydroxypropylcellulose, sodium starch glycolate. The disintegrant and / or swelling agent may preferably be present in an amount of 1-50% by weight based on the total weight of the composition.

[0035] The solubilizer may preferably be selected from poloxamers, sodium lauryl sulfate, polysorbates, polyoxylated oleic acid glycerides, glycerol monostearate, and cyclodextrins. The solubilizer may preferably be present in an amount of up to 30% by weight relative to the total weight of the composition.

[0036] The enteric release agent may preferably be selected from hydroxypropylmethylcellulose phthalate, poly(methacrylic acid-co-methyl methacrylate), cellulose acetate phthalate, poly(vinyl acetate phthalate), esters of aryl acids. The enteric release agent may preferably be present in an amount of 2-40% by weight based on the total weight of the composition.

[0037] The mucoadhesive component may preferably be selected from propylene glycol alginate, sodium alginate, calcium alginate, potassium alginate, hydroxypropyl methylcellulose, carmellose sodium, polyacrylic acid, polyethylene oxide, povidone, and copovidone. The mucoadhesive component may preferably be present in an amount of 5 to 70% by weight based on the total weight of the composition.

[0038] The sustained release agent may preferably be selected from cellulose and cellulose ethers, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, polyvinyl acetate, alginic acid, propylene glycol alginate, sodium alginate, calcium alginate, potassium alginate, polymethacrylates, guar gum, xanthan gum, carrageenan, castor oil, beeswax, carnauba wax, glycerol palmitostearate, glycerol monostearate, glycerol behenate, stearyl alcohol, polyacrylic acid. The sustained release agent may preferably be present in an amount of 5-70% by weight relative to the total weight of the composition.

[0039] The oral pharmaceutical composition may, in some embodiments, further comprise a pharma- ceutically acceptable component capable of generating carbon dioxide upon contact with gastric fluids; such component may preferably be selected from alkali metal and alkaline earth metal carbonates and bicarbonates, and may preferably be present in an amount ranging from 1 to 50% by weight, based on the total weight of the composition.

[0040] A typical daily dose of rebamipide for an average human (body weight 70 kg) may range from 1 to 5000 mg, more preferably from 50 to 2500 mg, even more preferably from 100 to 1000 mg, and most preferably from 300 to 500 mg.

[0041] When administering immediate release formulations of rebamipide, the daily dose is usually divided into several doses, which are administered separately. The daily dose may be divided into 2 to 6 doses, and administered twice a day, three times a day, four times a day, five times a day, or six times a day. In a preferred embodiment, the daily dose is divided into three doses, and administered three times a day, in particular 100 mg doses three times a day. Alternatively, the entire daily dose may be administered in one dose, in particular when in the form of a sustained release formulation, for example 300 mg doses administered once a day. The duration of treatment is to be determined by the physician. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The present invention will be described in more detail below with reference to examples. However, the following examples are provided for illustrative purposes only and therefore the present invention is not limited thereto. EXAMPLES

[0043] Elimination provocation test A gluten challenge test was used to examine the effect of rebamipide on celiac disease. Adult patients who were stable on a gluten-free diet (GFD) and free of disease symptoms for at least 12 months were eligible to participate in the study. All participants had a previous physician-diagnosed celiac disease based on upper gastrointestinal endoscopy and duodenal biopsy. Adherence to the gluten-free diet was confirmed by a reduction in villus height to crypt depth ratio (Vh / Cd>2-3) and anti-tTG antibody levels (<10 U / mL) after elimination of gluten from the diet.

[0044] Patients were divided into two groups and received either 100 mg of rebamipide or a placebo three times daily immediately before meals. Both groups continued their gluten-free diet. A gluten challenge test was performed 3 months after the start of treatment (day 90). Patients were given one slice of white bread containing approximately 2.7 g of wheat gluten daily for 6 weeks while otherwise maintaining their usual gluten-free diet. Both groups continued their rebamipide or placebo treatment.

[0045] Celiac disease symptoms were assessed weekly using the Gastrointestinal Symptom Scale (GSRS) questionnaire, a widely used tool in the study of gastrointestinal diseases such as celiac disease (10). This consists of 15 questions categorized into five symptoms (diarrhea, abdominal pain, dyspepsia, constipation, and acid reflux), which are summed to give a total score and the average of all 15 items is calculated. Scores are based on a Likert scale ranging from 1 to 7 points, with 1 point representing almost no gastrointestinal symptoms and 7 points representing extremely severe symptoms.

[0046] Intestinal permeability was measured using standardized urinary lactulose / mannitol (La / Ma) fractional excretion ratios at the start of the study, before induction, and 6 weeks after induction. The La / Ma test is based on differences in the absorption of non-metabolized sugars. In the normal intestine, monosaccharides (e.g. mannitol) are passively absorbed through the intestinal mucosa, whereas large disaccharide molecules (e.g. lactulose) are usually poorly absorbed. In contrast, in patients with celiac disease, the increased intestinal permeability leads to a continuous increase in lactulose absorption (via the paracellular pathway) and the reduced surface area caused by villous atrophy leads to a decrease in mannitol absorption (via the transcellular pathway), resulting in a higher La / Ma ratio.

[0047] Duodenal biopsies were performed at the beginning (day 0) and end (day 132) of the study period. The villus height to crypt depth ratio (Vh / Cd) was determined by pathologists measuring the mean adjacent villus / crypt height / mean depth. A ratio <2 was considered to indicate villous atrophy and crypt hyperplasia.

[0048] Mean serum anti-tTG antibody levels were determined by enzyme-linked immunosorbent assay (ELISA), and differences were compared between baseline and 6 weeks after challenge.

[0049] The results are summarized in Table 1.

[0050] [Table 1]

[0051] The mean GSRS total score decreased during pretreatment with rebamipide and then gradually increased toward baseline values ​​during the gluten induction period. Meanwhile, the placebo group showed a rapid increase in GSRS score during the first week of the gluten induction period and remained high thereafter. Patients reported a variety of symptoms, including diarrhea, abdominal bloating, abdominal pain, and fatigue. The difference in GSRS scores between rebamipide and placebo showed that the mean GSRS score in the rebamipide-treated group was significantly lower than that in the placebo group (0.6 units at the end of the study). This means that the severity of symptoms was statistically significantly less in the group of patients who received rebamipide before and during the gluten induction test compared to the placebo group.

[0052] Although the fractional excretion ratio of La / Ma is known to vary widely among individuals, results show that the ratio of these sugars was significantly increased in the placebo group after daily gluten ingestion, suggesting increased intestinal permeability. In contrast, the La / Ma ratio in the rebamipide-treated group was close to baseline at the end of the gluten induction period, indicating activity against undesired increased intestinal permeability.

[0053] Beginning on day 0, all participants had normal Vh / Cd in small intestinal biopsies. However, after 6 weeks of daily gluten ingestion, the majority of patients in the placebo group showed histological changes. The mean Vh / Cd value worsened to 1.7, indicating active celiac disease. Surprisingly, the rebamipide group showed no unfavorable changes from baseline to post-treatment in the ratio of villus height to crypt depth, suggesting treatment success.

[0054] Mean anti-tTG IgA titers increased after gluten challenge but remained below the 10 U / mL threshold in the rebamipide-treated group. Although the mean antibody response was greater in the placebo group, some patients did not experience a measurable change in anti-tTG IgA titers over the gluten challenge period.

[0055] The results of the elimination challenge study show that rebamipide protects the intestinal mucosa from ingested gluten, reduces intestinal permeability, and improves the symptoms of celiac disease reported by patients. The drug allows gluten to be ingested without exacerbating the disease. This can dramatically improve the quality of life, as adherence to a strict gluten-free diet is difficult and expensive. Furthermore, accidental gluten ingestion cannot be completely avoided, and even products labeled as gluten-free may contain traces of gluten. It can be concluded that rebamipide offers an unparalleled opportunity in celiac disease management, improving the quality of life of patients and potentially resulting in long-term remission of celiac disease.

Claims

1. A pharmaceutical composition comprising rebamipide for use in the prevention and / or treatment of celiac disease.

2. Rebamipide for the prevention and / or treatment of celiac disease in individuals adhering to a gluten-free diet The pharmaceutical composition of claim 1.

3. A pharmaceutical composition comprising rebamipide, A pharmaceutical composition for use in a method for suppressing increased intestinal permeability due to gluten sensitivity.

4. Use of rebamipide for the prevention and / or treatment of celiac disease in individuals with or at risk of having increased intestinal permeability The pharmaceutical composition of claim 1.

5. Using rebamipide as a method to prevent celiac disease A pharmaceutical composition according to any one of claims 1 to 4.

6. The person with increased intestinal permeability has at least one condition selected from mild inflammation of the intestinal wall, chronic constipation, or gastroparesis. A pharmaceutical composition according to claim 4 or 5.

7. The person at risk of increased intestinal permeability is a person suffering from stress, an unbalanced diet, or a bacterial, viral, or parasitic infection. A pharmaceutical composition according to claim 4 or 5.

8. The person at risk of increased intestinal permeability is a person who is exposed to at least one substance selected from nonsteroidal anti-inflammatory drugs, alcohol, nicotine, food additives, chemotherapeutic drugs, and antibiotics. A pharmaceutical composition according to claim 4 or 5.

9. Rebamipide is administered simultaneously or sequentially with nonsteroidal anti-inflammatory drugs, chemotherapy drugs, or antibiotics. The pharmaceutical composition according to claim 8.

10. Rebamipide is administered to people who abuse drugs such as alcohol and nicotine. The pharmaceutical composition according to claim 8.

11. The person at risk of increased intestinal permeability has or is exposed to at least one condition selected from stress gastritis, food poisoning, cholic acid imbalance, gastric HCl and pepsin secretion, non-infectious diarrhea, radiation therapy, chemotherapy, infectious or post-infectious disorders of the GIT mucosa, and microbial dysbiosis. A pharmaceutical composition according to claim 4 or 5.

12. Rebamipide is administered in an oral dosage form, preferably selected from tablets, capsules, sugar-coated tablets, granules, sachets, orodispersible tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, mouthwashes, and mouthwashes, or in a rectal dosage form, preferably selected from suppositories and enemas. A pharmaceutical composition according to any one of claims 1 to 11.

13. The oral dosage form is in the form of enteric release, preferably enteric sustained release or enteric controlled release.

13. The pharmaceutical composition of claim 12.

14. The dosage form comprises rebamipide and at least one pharma- ceutically acceptable excipient selected from a filler, a binder, a lubricant, a flow agent, a disintegrant / swelling agent, a solubilizer, an enteric release agent, a mucoadhesive component, a sustained release agent, a preservative, a coating, and a coloring agent. The pharmaceutical composition of claim 13.

15. Rebamipide is administered in a daily dose of 1 to 5000 mg, more preferably 50 to 2500 mg, even more preferably 100 to 1000 mg, and most preferably 300 to 500 mg. A pharmaceutical composition according to any one of claims 1 to 14.

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