Pharmaceutical composition containing rebamipide for use in the prevention and treatment of Crohn's disease

Abstract

Provided is rebamipide for use in a method for preventing and / or treating Crohn's disease. In particular, rebamipide is used for preventing and / or treating Crohn's disease in individuals with or at risk of having increased intestinal permeability.

Description

[Technical field]

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

[0002] Crohn's disease (CD), a member of the inflammatory bowel disease (IBD) family, is a chronic multifactorial disease involving genetic, environmental, and microbial factors. Although the exact cause is unknown, it is believed that the disease is triggered by environmental factors that disrupt the mucosal barrier, alter the healthy balance of the intestinal microbiota, and abnormally stimulate the intestinal immune response. This leads to chronic inflammation of the intestinal tract, with typical symptoms including diarrhea, weight loss, fatigue, rectal bleeding, and abdominal pain.

[0003] The disease can develop at any age, but usually begins in the second or third decade of life. It is estimated that it affects approximately 3 per 1,000 people in Europe and North America, with an equal incidence in men and women. It most commonly affects the terminal small intestine and the beginning of the large intestine, but can occur anywhere in the gastrointestinal tract, from the mouth to the anus. Discontinuous lesions and patchy inflammation are typical findings of CD.

[0004] There is currently no cure for Crohn's disease, and current treatments aim to alleviate the inflammation that causes symptoms. Over the years, several classes of drugs have been developed to treat CD. The choice of drug depends on the site of inflammation, the severity of the disease, comorbidities, and the patient's response to medical treatment. Mild cases can be treated with 5-aminosalicylates alone or in combination with antibiotics, but many patients eventually require corticosteroids to suppress symptoms. Although these help to reduce inflammation and induce remission, their long-term use is well known to be associated with side effects, and therefore they are not recommended as maintenance therapy. Furthermore, discontinuing corticosteroids leads to a worsening of the disease in approximately half of patients. Immunosuppressants such as thiopurines and methotrexate are often prescribed for patients who are resistant or dependent on corticosteroids, but these drugs have a slow onset of action, severe side effects, and clinical remission rates of approximately 40%.

[0005] Biologic therapy with monoclonal antibodies against TNFα, such as infliximab (Remicade) or adalimumab (Humira), is used in patients who do not respond to conventional treatment with corticosteroids and immunosuppressants. Other options include antibodies against interleukins, such as ustekinumab (Stelara), which acts as an antagonist of human IL-12 and IL-23, and human integrin-binding antibodies, such as vedolizumab (Entyvio), which targets integrin α4β7 and exerts gut-selective anti-inflammatory activity. Monoclonal antibodies have a relatively rapid onset of action and promote mucosal healing, but up to 30% of patients do not respond to treatment (primary nonresponders), and up to 50% of patients who initially respond to these agents lose response to treatment within 12 months (secondary nonresponders), which may require dose escalation or therapy modification. Monotherapy is considered relatively safe, but patients are more susceptible to infections and are at higher risk of malignancies. Furthermore, treatment discontinuation in patients in sustained remission remains a persistent problem.

[0006] Although some of the above-mentioned treatments can provide long-term relief of disease symptoms, the majority of CD patients ultimately require surgery. Therefore, there remains a high unmet medical need for a treatment that suppresses intestinal inflammation and provides a sustained complete remission of disease symptoms. To address this need, the present invention provides an inexpensive treatment suitable for both induction and maintenance therapy of CD.

[0007] 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 gastric ulcers. Its mechanism of action involves mucosal defense, scavenging of free radicals, and transient activation of the gene encoding cyclooxygenase-2. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Diao L et al.Rebamipide suppresses diclofenac-induced intestinal permeability via mitochondrial protection in mice.World J Gastroenterol.2012;18(10):1059-1066 [Non-Patent Document 2] Katz KD et al.Intestinal permeability in patients with Crohn's disease and their healthy relatives.Gastroenterology.1989;97(4):927-931 [Non-Patent Document 3] Irvine EJ & Marshall JK.Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk.Gastroenterology.2000;119(6),1740-1744 [Non-Patent Document 4] Sequeira IRet al.(2014)PLoS One;9(6):e99256 Summary of the Invention [Problem to be solved by the invention]

[0009] It has been unexpectedly found that administration of rebamipide to patients with Crohn's disease can suppress disease symptoms and may even lead to complete remission of the disease. This is quite surprising, since rebamipide, which is clinically used only to treat gastrointestinal disorders, has not been reported to be effective in Crohn's disease, which is primarily manifested in the intestinal tract. Although rebamipide has been commercially available since 1990, little is known about its behavior in the gastrointestinal tract. As this molecule is poorly absorbed in the gastrointestinal tract, oral administration is likely to reach the intestinal mucosa in sufficient concentrations to exert a therapeutic effect. Nevertheless, to the best of our knowledge, there have been no reports that oral administration of rebamipide is effective in treating Crohn's disease.

[0010] The mechanism of action of rebamipide is likely based on its ability to promote mucin production in the intestine, suppress inflammation, and restore tight junction function in epithelial cells, thereby reducing intestinal wall permeability and normalizing intestinal function (Non-Patent Document 1). This leads to the suppression of chronic inflammation and intestinal recovery, preventing further tissue damage, and alleviating disease symptoms. In fact, increased small intestinal permeability to various agents is frequently seen in patients with Crohn's disease (Non-Patent Document 2), and has been reported to precede the onset of the disease in people with a genetic predisposition (Non-Patent Document 3). [Means for solving the problem]

[0011] Thus, the present invention provides rebamipide or a pharmaceutical composition thereof for use in a method for the prevention and / or treatment of Crohn's disease, particularly by reducing intestinal permeability. The method may advantageously be used in induction therapy to reduce inflammation, alleviate symptoms, and / or bring about remission as defined below, and / or in maintenance therapy to prevent relapse or recurrence of the disease in those who have achieved remission.

[0012] 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.

[0013] "Prevention" or "prophylactic use" is understood herein to mean preventing or delaying the onset of disease and its symptoms, including recurrence in patients who have undergone a previous treatment and are in complete or partial remission. It also includes the maintenance of remission and / or lack of worsening of disease symptoms after tapering or cessation of previous treatment. It also includes the prevention of disease complications such as intestinal obstruction, ulcers and fistulas, anal fissures, colon cancer, arthritis, uveitis, erythema nodosum, pyoderma gangrenosum, or aphthous stomatitis.

[0014] "Treatment" is herein understood as a therapy that can prevent, arrest, slow or reverse the progression of the disease and / or suppress chronic inflammation in the small intestine or elsewhere in the digestive tract. It is also intended to include the improvement or alleviation of clinical symptoms of the disease, such as abdominal pain, diarrhea, abdominal bloating, bloody stools, stomatitis, fatigue, loss of appetite and weight loss, malnutrition, dermatitis, etc.

[0015] The present invention further provides a method for preventing and / or treating Crohn's disease by administering a pharma- tically 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. The present invention further includes the use of rebamipide in the manufacture of a medicament for preventing and / or treating Crohn's disease, particularly in a person with or at risk of having increased intestinal permeability.

[0016] In one embodiment, rebamipide is used in a method for the prevention and / or treatment of Crohn's disease in individuals with or at risk for increased intestinal permeability, for example, because of a family history of the condition or exposure to conditions or substances that induce increased intestinal permeability.

[0017] 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 Crohn's disease, as well as chronic constipation and gastroparesis. Intestinal permeability may be diagnosed using specific tests, such as the lactulose-mannitol test (LAMA test, e.g., Non-Patent Document 4), 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 of greater than 4 angstroms.

[0018] 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 Crohn's disease associated with increased intestinal permeability.Prophylactic use of rebamipide may also be beneficial for those 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.

[0019] 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).

[0020] 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.

[0021] In one embodiment, rebamipide is used in combination therapy with at least one other drug effective against Crohn's disease, and the other drug can be administered simultaneously, separately, or sequentially with rebamipide.Preferably, the combination therapy is used in the treatment of active Crohn's disease.More preferably, the combination therapy is used in the maintenance therapy to reduce inflammation, alleviate symptoms, and / or bring about remission.

[0022] The term drug is meant to include both small molecules, i.e. those with a molecular weight of less than about 900 g / mol, and macromolecules, particularly antibodies.The at least one other drug effective against Crohn's disease is preferably selected from 5-aminosalicylate, corticosteroids, immunosuppressants, antibiotics, and antibodies.More preferably, the other drug is selected from corticosteroids, immunosuppressants, and antibodies.Most preferably, the other drug is a corticosteroid.

[0023] 5-aminosalicylates are anti-inflammatory chemotherapeutic agents that are primarily used to manage mild to moderate Crohn's disease. These compounds include mesalazine (i.e., 5-aminosalicylic acid, 5-ASA, or mesalamine) and its complex derivatives, such as sulfasalazine, olsalazine, and balsalazide, that are known for their anti-inflammatory properties. Preferably, the 5-aminosalicylates are selected from mesalazine and sulfasalazine.

[0024] Corticosteroids are a type of anti-inflammatory drug, and are used to reduce inflammation in the digestive tract and relieve symptoms.The corticosteroids used in combination with rebamipide according to the present invention are preferably selected from prednisone, prednisolone, methylprednisolone, hydrocortisone, or budesonide.Advantageously, they can be further combined with at least one thiopurine to form a triple combination.The corticosteroids can be administered orally, rectally, or intravenously.

[0025] In one embodiment, the corticosteroid is in an oral formulation (e.g., tablet or capsule). This dosage form is usually administered to people with mild to moderate active disease. Advantageously, oral budesonide is also used for mild to moderate disease affecting the terminal small intestine to the beginning of the large intestine.

[0026] In another embodiment, the corticosteroid is in a rectal formulation (e.g., suppository, enema, or rectal form), preferably selected from hydrocortisone, methylprednisolone, and budesonide. Rectal formulations are particularly suitable for people with active disease in the lower part of the colon or rectum. They specifically target the affected areas, and therefore have fewer side effects than oral formulations.

[0027] In another embodiment, the corticosteroid is administered intravenously and is preferably selected from hydrocortisone and methylprednisolone. Intravenous administration is particularly suitable for patients with severe active disease.

[0028] Immunosuppressants are drugs that inhibit the activity of the immune system, thereby reducing inflammation.Preferably, they are selected from thiopurines, methotrexate, cyclosporine, and tacrolimus. Thiopurines and methotrexate are particularly preferred. Thiopurines are purine antimetabolites, preferably selected from azathioprine and 6-mercaptopurine.Advantageously, they can be combined with rebamipide and at least one corticosteroid or at least one antibody to form a triple combination.

[0029] Antibiotics are primarily used in mild to moderate disease, reducing the amount and altering the composition of intestinal bacteria, thereby relieving symptoms. They are also used to manage infections and complications of Crohn's disease, such as abscesses, fistulas, and pouchitis. Preferably, the antibiotic is selected from metronidazole, ciprofloxacin, rifaximin, and ampicillin. Metronidazole and ciprofloxacin, especially in intravenous infusion form, are particularly preferred.

[0030] Antibodies (biologics) are protein molecules that target specific mediators of disease, such as cytokines or integrins. They may be of any origin, such as human or murine, including humanized and chimeric antibodies. As used herein, the term "antibody" refers to antigen-binding fragments of antibodies, i.e., F(ab')2, Fab, Fab', Fv, and sc It is intended to include fragments containing the variable regions of antibodies, such as Fv fragments, as well as derivatives which have been chemically altered, for example pegylated.

[0031] In one embodiment, the antibody is selected from antibodies against TNFα, preferably from infliximab, adalimumab, golimumab, certolizumab pegol, and biosimilars thereof. More preferably, the antibody is selected from infliximab, adalimumab, and biosimilars thereof.

[0032] In another embodiment, the antibody is selected from antibodies against interleukins, such as IL-12 and / or IL-23. Preferably, the antibody is ustekinumab or a biosimilar thereof.

[0033] In yet another embodiment, the antibody is selected from antibodies against integrins, in particular integrin α4β7. Preferably, the antibody is selected from natalizumab, vedolizumab, and biosimilars thereof. More preferably, the antibody is vedolizumab or a biosimilar thereof.

[0034] More specifically, the combination therapy with at least one other drug effective against Crohn's disease defined above comprises the steps of administering rebamipide to a person undergoing treatment with a dose of at least one other drug effective against Crohn's disease; and reducing the dose of the other drug.

[0035] Advantageously, the combination therapy comprises administering rebamipide as an add-on to a treatment with at least one other drug effective against Crohn's disease, in particular 20-60 mg of prednisone or an equivalent dose of another corticosteroid; and reducing the dose of said other drug.

[0036] In one embodiment, the dose of the other agent is tapered at the initiation of rebamipide administration, ie, at the same time that the patient begins receiving rebamipide.

[0037] In another embodiment, the dose of the other agent is reduced following symptomatic improvement, defined as a reduction in CDAI of more than 100 points or a reduction in fecal calprotectin of more than 150 μg / g.

[0038] At least one other agent may be discontinued completely after the patient reaches remission, defined as endoscopy (mucosal healing) and / or CDAI <150 (clinical remission) and / or fecal calprotectin <200 μg / g (suppression of inflammation).

[0039] Combination therapy may advantageously be used to save the dose of other drugs, in particular corticosteroids, to prevent adverse effects.Accordingly, the present invention further provides rebamipide for use in a method for saving the dose of at least one other drug effective against Crohn's disease.The method advantageously comprises the steps of administering rebamipide to a person undergoing treatment with a dose of the other drug effective against Crohn's disease, preferably 20-60 mg of prednisone or an equivalent dose of another corticosteroid; and reducing the dose of the other drug.

[0040] In one embodiment, rebamipide is used as monotherapy. That is, the subject to be treated receives only rebamipide and does not receive any other effective drug against Crohn's disease.Preferably, rebamipide monotherapy is used in the method of preventing Crohn's disease, including preventing the first onset in people who are susceptible to Crohn's disease, for example, because they have or are at risk of having increased intestinal permeability, and / or preventing disease relapse or recurrence in people who have reached remission as defined above in response to induction therapy.More preferably, rebamipide monotherapy is used in the maintenance therapy of Crohn's disease, to prevent inflammation and / or maintain remission.

[0041] The present invention further provides a combination of treatments comprising rebamipide and at least one other drug effective against Crohn's disease. The term drug is meant to include both small molecules, i.e. those with a molecular weight of less than about 900 g / mol, and large molecules, such as antibodies, preferably selected from TNFα, interleukins, or integrins, such as integrin α4β7. The at least one other drug is selected from 5-aminosalicylates, preferably sulfasalazine or mesalazine; corticosteroids, preferably prednisone, prednisolone, methylprednisolone, hydrocortisone, or budesonide; immunosuppressants, preferably azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus; antibiotics, preferably metronidazole and ciprofloxacin; and antibodies (biologicals), preferably infliximab, adalimumab, vedolizumab, and their biosimilars.

[0042] In a preferred embodiment, the combination comprises rebamipide and at least one other agent selected from a corticosteroid, a thiopurine, and an antibody. In a more preferred embodiment, the present invention provides a therapeutic combination comprising rebamipide and at least one corticosteroid, in particular 20-60 mg of prednisone or an equivalent dose of another corticosteroid.

[0043] In the therapeutic applications described in the present invention, rebamipide may be preferably used in dosage forms for oral administration such as tablets, capsules, sugar-coated tablets, granules, microgranules (sachets), orodispersible tablets or films, sublingual tablets, pulverized tablets, oral liquids, oral suspensions, syrups, mouthwashes, or mouthwashes. 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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 to 20% by weight relative to the total weight of the composition.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] The oral pharmaceutical composition, in some embodiments, further comprises a pharma- ceutically acceptable ingredient capable of generating carbon dioxide upon contact with gastric fluids; such ingredient 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.

[0056] 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 600 mg or 300 to 900 mg.

[0057] When administering an immediate release formulation 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, for example, a 100 mg dose administered three times a day. Alternatively, the entire daily dose may be administered in one dose, particularly when in the form of a sustained release formulation, for example, a 300 mg dose administered once a day. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] 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

[0059] Patients with Crohn's disease for more than five years who had not responded adequately to standard treatment were administered rebamipide tablets three times daily. These patients had extensive treatment histories with a variety of medications, but were unable to achieve remission after disease flares with standard options. Severity was quantified by CDAI and inflammation by fecal calprotectin.

[0060] The Crohn's Disease Activity Index (CDAI) is a survey instrument used to quantify symptoms in patients with Crohn's disease. It consists of eight items, which are summed after adjusting for weighting. Remission of Crohn's disease is defined as a CDAI less than 150, whereas a CDAI greater than 450 is defined as severe.

[0061] Calprotectin (FC) is a small calcium-binding protein that has been used as a biomarker for inflammatory bowel disease because fecal concentrations correlate with disease severity. Fecal calprotectin levels below 200 μg / g are considered normal. It was measured in stool samples using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (EK-CAL, Buhlmann). EXAMPLES

[0062] A female patient (39 years old) diagnosed with Crohn's ileocolitis 16 years ago had been treated with a variety of medications during the course of her disease, including oral, parenteral, and topical corticosteroids, azathioprine, and the TNFα inhibitors infliximab and adalimumab. An immune reaction to these antibodies occurred, affecting the skin and joints, and she was switched to vedolizumab (Entyvio), which remained stable for the next 22 months. During disease flare-ups, the patient presented with abdominal pain, increased bowel movements, arthralgia, myalgia, low-grade fever, fatigue, dry dermatitis, fecal calprotectin levels up to 1939 μg / g, and CDAI of 358. Treatment was continued with methylprednisolone 24 mg / day without success. Rebamipide 100 mg three times daily was started in conjunction with corticosteroid treatment, and after 6 weeks of treatment, disease symptoms were alleviated (CDAI 181) and calprotectin levels decreased to 228 μg / g, rapidly resulting in remission. The corticosteroid dose was then halved without any adverse effects. After a further 6 weeks, when calprotectin levels had decreased to 63 μg / g and CDAI to 73, corticosteroids were discontinued completely, and rebamipide alone was continued. To date, there has been no worsening of disease activity. EXAMPLES

[0063] A male patient (27 years old) diagnosed with Crohn's ileocolitis 5 years ago was treated with mesalazine (Pentasa), budesonide, and metronidazole. The patient developed pancreatitis 3 months after starting mesalazine treatment. The medication was subsequently changed to azathioprine in combination with prednisone and then to methotrexate. However, the pharmacotherapy was not well tolerated, and biologic therapy was indicated. The patient was treated with infliximab (Remicade) followed by adalimumab (Humira). After a final flare (calprotectin 2215 μg / g, CDAI 479), he was treated with prednisone 40 mg / day but did not achieve remission. Rebamipide 200 mg 3 times daily was started as an add-on to prednisone. After 6 weeks (calprotectin 356 μg / g, CDAI 225), rebamipide was adjusted to 100 mg three times daily and prednisone to 30 mg daily. The prednisone dose was then reduced by 10 mg every 2 weeks and discontinued completely after 6 weeks (calprotectin 110 μg / g, CDAI 84). Rebamipide 100 mg three times daily was continued. To date, there has been no worsening of disease activity. EXAMPLES

[0064] A female patient (32 years old) diagnosed with Crohn's ileitis 12 years ago was treated with budesonide and mesalazine and maintained remission for about 10 years. She was then admitted with abdominal pain 3-4 times a day and loose stools, at which time her calprotectin level was up to 1051 μg / g and her CDAI was 377 points. Azathioprine was prescribed, but was discontinued 2 weeks later due to acute pancreatitis. Treatment was continued with a combination of prednisone 50 mg / day and rebamipide 100 mg three times a day. As clinical symptoms were alleviated, the prednisone dose was adjusted to 25 mg after 14 days, and after another 6 weeks, the calprotectin level had decreased to 122 μg / g and the CDAI to 98 points, at which point the drug was completely discontinued, and rebamipide alone was continued. To date, there has been no worsening of disease activity.

[0065] Our case-based results show that rebamipide is able to control disease symptoms, normalize calprotectin levels, and induce remission, even in patients who have exhausted standard treatment options. Although the treatment was initiated as an add-on to corticosteroids for ethical reasons, it appears to be effective even when prescribed as monotherapy. Importantly, corticosteroid treatment alone was unable to completely suppress disease symptoms or reduce fecal calprotectin levels to <200 μg / g and CDAI <150. Furthermore, long-term treatment with rebamipide alone appears to be well tolerated and maintains remission.

Claims

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

2. The method includes combining rebamipide with at least one other drug effective against Crohn's disease. The pharmaceutical composition of claim 1.

3. The method includes the steps of administering rebamipide to a person who is being treated with a dose of at least one other drug effective against Crohn's disease; and reducing the dose of the other drug. The pharmaceutical composition according to claim 2.

4. Reduce the dose of the other drug when starting rebamipide administration. The pharmaceutical composition according to claim 3.

5. After symptoms improve, the dose of the other drug is reduced. The pharmaceutical composition according to claim 3.

6. Discontinuing the other medication after the person has achieved remission. A pharmaceutical composition according to any one of claims 2 to 5.

7. Rebamipide used in the treatment of Crohn's disease A pharmaceutical composition according to any one of claims 1 to 6.

8. The method includes administering rebamipide to a person with active Crohn's disease to induce remission. The pharmaceutical composition according to claim 7.

9. The method is a monotherapy The pharmaceutical composition of claim 1.

10. Using rebamipide as a preventative method for Crohn's disease The pharmaceutical composition according to claim 9.

11. The method includes administering rebamipide to a person in remission of the disease to prevent relapse and / or recurrence of the disease. A pharmaceutical composition according to claim 9 or 10.

12. A pharmaceutical composition comprising: A pharmaceutical composition for use in the prevention and / or treatment of Crohn's disease, comprising rebamipide and at least one other drug effective against Crohn's disease.

13. The other drugs are selected from 5-aminosalicylates, preferably selected from sulfasalazine and mesalazine; corticosteroids, preferably selected from prednisone, prednisolone, methylprednisolone, hydrocortisone, and budesonide; immunosuppressants, preferably selected from thiopurines, methotrexate, cyclosporine, and tacrolimus; antibiotics, preferably selected from metronidazole and ciprofloxacin; and antibodies, preferably selected from infliximab, adalimumab, vedolizumab, and biosimilars thereof. A pharmaceutical composition comprising a combination of a pharmaceutical composition according to any one of claims 2 to 8 or a pharmaceutical composition according to claim 12.

14. The other drug is selected from a corticosteroid, an immunosuppressant, and an antibody. The pharmaceutical composition of claim 13.

15. The other agent is a corticosteroid, preferably 20-60 mg of prednisone or an equivalent dose of another corticosteroid. A pharmaceutical composition according to claim 13 or 14.

16. Rebamipide is used for the prevention and / or treatment of Crohn's disease in individuals with or at risk for increased intestinal permeability. A pharmaceutical composition according to any one of claims 1 to 15.

17. The person with increased intestinal permeability has at least one condition selected from mild inflammation of the intestinal wall, chronic constipation, or gastroparesis.

17. The pharmaceutical composition of claim 16.

18. The person at risk of increased intestinal permeability is a person suffering from stress, an unbalanced diet, or a bacterial, viral, or parasitic infection.

17. The pharmaceutical composition of claim 16.

19. 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.

17. The pharmaceutical composition of claim 16.

20. 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.

17. The pharmaceutical composition of claim 16.

21. Rebamipide is preferably administered in an oral dosage form selected from tablets, capsules, sugar-coated tablets, granules, microgranules (sachets), orodispersible tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, mouthwashes, or mouthwashes.

21. A pharmaceutical composition according to any one of claims 1 to 20.

22. The oral dosage form is a tablet.

22. The pharmaceutical composition of claim 21.

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

23. A pharmaceutical composition according to claim 21 or 22.

24. 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.

23. A pharmaceutical composition according to claim 21 or 22.

25. 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 600 mg.

25. A pharmaceutical composition according to any one of claims 1 to 24.