Rebamipide for use in cancer prevention and treatment

Abstract

The present invention relates to rebamipide for use in the prevention and / or treatment of cancer in a person suffering from intestinal permeability or at increased risk of intestinal permeability (e.g., due to family memory loss or exposure to conditions or substances that increase intestinal permeability).

Description

Technology Field

[0001] The present invention relates to rebamipide for use in the prevention and / or treatment of cancer in people suffering from or at risk of increased intestinal permeability. Background Technology

[0002] Cancer is one of the leading causes of death worldwide, accounting for 25% of deaths in Europe. It is a disease caused by genetic changes that can be sporadic or hereditary, leading to uncontrolled cell growth and tumor formation. Most cancers are associated with environmental, lifestyle, or behavioral exposures. Common environmental factors contributing to cancer include high-energy radiation, including ultraviolet, X-rays, and gamma rays; tobacco smoke; alcoholic beverages; certain microorganisms and parasites; and various carcinogens such as various compounds.

[0003] As evidence grows that certain dietary habits increase the risk of cancer, diet is considered to play a significant role in the pathogenesis of cancer. These include diets that are high in glycemic load, rich in fat, and low in antioxidants. Additionally, certain types of food contain substances known to promote the development of cancer. These may be natural products or artificial chemicals that exist as contaminants or are intentionally added to food to act as preservatives, colorings, or flavorings.

[0004] Low-grade chronic inflammation is another significant risk factor for cancer development. The inflammatory microenvironment, composed of various immune cells, epithelial cells, stromal cells, cytokines, and chemokines, shares many similarities with the cancer microenvironment, suggesting similar inflammatory mediators and mechanisms that promote chronic inflammation and cancer development. These mediators produced by inflammatory cells include tumor necrosis factor alpha (TNF-α) and ILs-1, 6, 12, 13, 17, 22, and 23. The precise molecular mechanisms underlying the transition from inflammation to cancer have not yet been fully elucidated. Current evidence suggests that several factors play a role in cancer development, such as immune responses, activation of oncogenes, inhibition of tumor suppressor factors, alterations in normal microRNA expression patterns, changes in the epigenetic environment, and commensal microbes and corresponding inflammatory responses in epithelial cells.

[0005] Although significant resources have been utilized for the development of cancer treatments, no effective cure has yet been discovered. Consequently, there is a high, unmet medical need for new medicines that can be used to treat or prevent cancer.

[0006] Rebamipide, chemically 2-[(4-chlorobenzoyl)amino]-3-(2-oxo-1H-quinoline-4-yl)propanoic acid, is used in the treatment of 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.

[0007] Within the framework of the present invention, rebamipide has been found to prevent and / or treat cancer associated with increased intestinal permeability. Under normal physiological conditions, the intestinal barrier acts as a barrier that is effective for nutrient absorption but prevents harmful molecules and microorganisms from entering the body from within the intestines. However, if the barrier is damaged for any reason, it fails to function properly, allowing substances that should normally remain in the intestinal lumen to pass into the body. Since the human diet contains not only nutrients but also potentially carcinogenic substances found in burnt food, processed meat, or red meat, increased intestinal permeability becomes a serious risk factor for cancer development. Furthermore, when undesirable foreign substances pass through the intestinal mucosa and into the body, the immune system is activated, leading to the secretion of inflammatory mediators and consequently causing chronic intestinal inflammation (often asymptomatic), thereby contributing to both intestinal permeability and cancer development.

[0008] The presumed mechanism of action of rebamipide may be based on its ability to induce mucin production in the intestine, suppress inflammation, and restore the tight junction function of epithelial cells, thereby reducing the permeability of the intestinal barrier. This leads to the recovery of the intestine, and consequently, the intestinal immunological barrier is restored, preventing further tissue damage caused by toxins or pathogens present in the gastrointestinal tract, thereby preventing chronic inflammation and subsequent development of malignant tumors in the gastrointestinal tract or other parts of the body.

[0009] Accordingly, the present invention provides rebamipide for use in a method of preventing and / or treating cancer in a person suffering from increased intestinal permeability or a person at risk of increased intestinal permeability due, for example, to a family history or exposure to conditions or substances that increase intestinal permeability. In a preferred embodiment, rebamipide is intended for use in a method of preventing cancer, particularly in cases involving diet or intestinal inflammation.

[0010] "Rebamipide" as used in the present invention will include all forms of such active ingredients, e.g., anhydrous form, hydrated or solvated form (e.g., hemihydrate form), crystalline form; and pharmaceutically acceptable salts thereof.

[0011] As used herein, "cancer" refers to a group of diseases involving abnormal cell growth that has the potential to invade or spread to other parts of the body. Specifically, the invention relates to cancer associated with increased intestinal permeability, a condition in which carcinogens present in the gastrointestinal tract pass into the normal body and contribute to the development of malignant tumors. These carcinogens can directly induce cancer growth in the intestines and / or surrounding tissues, but may also occur in more distant organs and tissues. The underlying mechanism of this phenomenon lies in the ability of carcinogens to spread to distant parts of the body via the bloodstream.

[0012] "Carcinogens" are substances and mixtures thereof that, upon entering the body, can trigger a process leading to the development of cancer. This may be attributed to their ability to damage the genome or disrupt cellular metabolic processes. These form heterogeneous groups classified by the International Agency for Research on Cancer (IARC) based on the strength of the evidence of carcinogenicity. Some substances may be carcinogenic in themselves, while others may become carcinogenic only after being metabolized in the intestines or other parts of the body. The present invention preferably relates to carcinogens that cannot or do not pass through the intestinal wall at a relatively low rate under normal physiological conditions, but whose passage into the normal body increases substantially in cases suffering from increased intestinal permeability.

[0013] In one embodiment, the present invention provides rebamipide for use in a method for the prevention and / or treatment of diet-related cancer. Diet-related cancer is a malignant tumor caused by carcinogens present in food, whether naturally occurring, caused by contamination, or intentionally added as food additives. People suffering from or at risk of increased intestinal permeability are more sensitive to various foodborne carcinogens, such as those found in burnt food, processed meat, or red meat.

[0014] Processed meat refers to meat whose flavor or shelf life has been enhanced through processing such as salting, curing, fermentation, or smoking. The IARC has classified this as a Group 1 carcinogen, meaning it is carcinogenic to humans. Red meat refers to the muscular meat of all mammals, including cattle, veal, pigs, sheep, mutton, horses, and goats, and has been classified as a Group 2A carcinogen, meaning it is possibly carcinogenic to humans. Current research indicates that these foods contain additional and naturally occurring carcinogens, including acrylamide and polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluorantene, and chrysene; It shows that it includes heterocyclic aromatic amines (HCAs), e.g., 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimiazo[4,5-b]pyridine (PhIP); and N-nitrosamines, e.g., N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-nitrosodi-N-butylamine, N-nitrosodiethylamine (DEN), N-nitrosodimethylamine (NDMA), N-nitrosopiperidine, N-nitrosopyrrolidine, and N-nitrosasarcosine.

[0015] Other carcinogens that enter the gastrointestinal tract and cause diet-related cancers originate from microbial contamination of food, which plays a role in producing various and often carcinogenic toxins, such as mycotoxins like aflatoxin, ochratoxin, and fumonisin. Additionally, certain microorganisms present in the gastrointestinal tract can produce and release various carcinogenic compounds, such as nitrosamines, in their place.

[0016] Food may also be contaminated by many other compounds that can directly or indirectly cause cancer, including pesticide residues, aromatic compounds, e.g., benzene, polychlorinated and polybrominated dibenzodioxins, dibenzofurans and biphenyls, e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin, heavy metals, e.g., lead, arsenic, cadmium and their compounds, and compounds released from packaging materials, e.g., formaldehyde, vinyl chloride or bisphenol A.

[0017] Cancers to be treated according to the present invention include both intestinal and non-intestinal malignancies. Intestinal malignancies form a group of cancers affecting the small intestine, colon, rectum, and anus and include adenocarcinoma, squamous cell tumor, carcinoid tumor, intestinal lymphoma, gastrointestinal stromal tumor, leiomyosarcoma, and melanoma. However, they may also affect adjacent tissues such as the pancreas, liver, and gallbladder. In a preferred embodiment, intestinal cancer is selected from small intestine cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer, and cholangiocarcinoma. Non-intestinal malignancies include oral cancer, pharyngeal cancer, salivary gland cancer, esophageal cancer, gastric cancer, breast cancer, prostate cancer, ovarian cancer, bladder cancer, lung cancer, skin cancer, vascular cancer, hematopoietic cancer, B-cell lymphoma, and thyroid cancer.

[0018] "Increased intestinal permeability" is used herein as a term designating minor intestinal barrier defects, including those caused by asymptomatic chronic inflammation of the intestinal barrier (low-grade inflammation). Such intestinal barrier defects may manifest, for example, due to chronic constipation or gastroparesis. Increased intestinal permeability is indicated by the lactulose-mannitol test (LAMA test; e.g., Sequeira IR et al. (2014) PLoS OneIt can be diagnosed using specific tests such as the A-1-AT test or the zonulin test (9(6):e99256). Typically, increased intestinal permeability is the permeability of the barrier to particles with a radius greater than 4 angstroms. Therefore, co-administration of rebamipide with nonsteroidal anti-inflammatory drugs, chemotherapy agents, or antibiotics, either simultaneously or sequentially, can prevent barrier damage and thus prevent or delay the development of cancers associated with increased intestinal permeability. The prophylactic use of rebamipide may also be useful for individuals who abuse alcohol, nicotine, or other drugs known to damage the intestinal barrier. As used herein, the term "abuse" is intended to include any consumption that is not required for medical reasons and results in health impairment, including dependence and / or low-grade inflammation of the intestinal barrier.

[0019] Substances that induce increased intestinal permeability include nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, diclofenac, ketorolac, etodolac, indobetacin, tolmetine, piroxicam, meloxicam, and selective COX-2 inhibitors, e.g., celecoxib and etoricoxib; alcohol; nicotine; food additives; antibiotics; and chemotherapy.

[0020] Conditions that increase intestinal permeability are associated with stress, an unbalanced diet, allergies, bacterial, viral, or parasitic infections, and various medical treatments. These conditions include, in particular, stress-induced gastritis, digestive toxicity, cholinergic acid imbalance, gastric HCl and pepsin secretion, non-infectious diarrhea, radiation therapy, chemotherapy, infectious or post-infectious damage to the GIT mucosa, and microbiota (e.g., caused by antibiotic treatment).

[0021] In one embodiment, the present invention provides rebamipide for use in a method for the prevention and / or treatment of cancer in a person suffering from chronic intestinal inflammation, including low-grade inflammation of the intestinal wall. Preferably, the cancer is selected from colorectal cancer, small intestinal adenocarcinoma, intestinal lymphoma, anal cancer, and cholangiocarcinoma. Most preferably, the cancer is colorectal cancer.

[0022] "Prevention" or "prophylactic use" should be understood herein as preventing or delaying the onset of disease, including recurrence, in patients who have achieved complete or partial remission following, for example, surgical treatment, chemotherapy, radiation therapy, or immunotherapy. This is also intended to include preventing or delaying the progression of disease. In such cases, rebamipide is administered to patients in the early or early stages of the disease to be treated to prevent or delay progression to the next stage. The prophylactic effect of rebamipide lies in its ability to prevent carcinogens and other toxins from passing into the normal body, thereby preventing the occurrence of cancer development.

[0023] "Treatment" shall be understood herein as a therapy capable of slowing, stopping, suppressing, or reversing a disease. It is also intended to include the reduction or alleviation of the clinical symptoms of the disease. "Slowing down" means reducing the progression of the disease, even if it cannot be completely stopped or reversed, whereas "stopping" means being able to completely halt the progression of the disease.

[0024] The present invention also provides a method for the prevention and / or treatment of cancer in a person suffering from increased intestinal permeability or at risk of increased intestinal permeability by administering a pharmaceutically effective dose of rebamipide or a pharmaceutical composition thereof to a subject requiring treatment. The subject is preferably a human subject, while the cancer is preferably related to diet or intestinal inflammation. Furthermore, the present invention includes the use of rebamipide for the manufacture of a drug for the prevention and / or treatment of cancer in a person with increased intestinal permeability or at risk of increased intestinal permeability.

[0025] In the therapeutic indications as described in the present invention, rebamipide may preferably be used in the form of an oral medication such as tablets, capsules, coated tablets, granules, microgranules (packets), orally dissolving tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, mouthwashes, or rinses. Alternatively, it may be used in the form of a rectal medication such as suppositories and enemas. Preferably, the oral medication forms such as tablets, capsules, coated tablets, and granules are of enteric release, such as enteric sustained-release or enteric controlled-release types.

[0026] The pharmaceutical form may contain one or more pharmaceutically acceptable excipients selected from fillers, binders, lubricants, lubricants, disintegrants / expanding agents, solubilizers, enteric release agents, mucosal adhesive components, sustained-release agents, preservatives, coating agents, and coloring agents. These excipients are known in the field of pharmaceutical formulations, and those skilled in the art may select excipients suitable for the relevant pharmaceutical form.

[0027] Suitable methods for manufacturing pharmaceutical forms and compositions include wet granulation or dry granulation processes of active agents, auxiliary substances, and components, or direct homogenization processes of active agents, auxiliary substances, and components.

[0028] The fillers may preferably be selected from sugar alcohols (e.g., mannitol, sorbitol, xylitol), lactose starch, pregelatinized starch, cellulose, silicified cellulose, calcium hydrogen phosphate, calcium phosphate, sucrose, and calcium sulfate. The fillers may preferably be present in an amount of 5 to 90 wt.% with respect to the total weight of the composition.

[0029] The binders may preferably be selected from starch, pregelatinized starch, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and cellulose. The binders may preferably be present in an amount of 1 to 20 wt.% with respect to the total weight of the composition.

[0030] The lubricants may preferably be selected from magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, and sodium stearyl fumarate. The lubricants may preferably be present in an amount of up to 5 wt.% of the total weight of the composition.

[0031] The lubricant may preferably be selected from silica, talc, and sodium lauryl sulfate. The lubricants may preferably be present in an amount of 0.5 to 10 wt.% with respect to the total weight of the composition.

[0032] The swelling agent and / or disintegrant may preferably be selected from crospovidone, copovidone, povidone, croscarmellose, hydroxypropyl methyl cellulose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch. The swelling agent / disintegrant may preferably be present in an amount of 1 to 50 wt.% with respect to the total weight of the composition.

[0033] Solubilizing agents may preferably be selected from poloxamer, sodium lauryl sulfate, polysorbate, polyoxylated oleic acid glyceride, glycerol monostearate, and cyclodextrin. Solubilizing agents may preferably be present in an amount of up to 30 wt.% of the total weight of the composition.

[0034] Enteric-releasing agents may preferably be selected from hydroxypropyl methylcellulose phthalate, poly(methacrylic acid-co-methyl methacrylate), cellulose acetate phthalate, poly(vinyl acetate phthalate), and esters of aleuritic acid. The enteric-releasing agents may preferably be present in an amount of 2 to 40 wt.% with respect to the total weight of the composition.

[0035] The mucosal adhesive components may preferably be selected from propylene glycol alginate, sodium alginate, calcium alginate, potassium alginate, hydroxypropyl methylcellulose, sodium carmellose, polyacrylic acid, polyethylene oxide, povidone, and copovidone. The mucosal adhesive components may preferably be present in an amount of 5 to 70 wt.% of the total weight of the composition.

[0036] Sustained-release agents may preferably be selected from cellulose and cellulose ethers, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, polyvinyl acetate, alginic acid, propylene glycol alginate, sodium alginate, calcium alginate, potassium alginate, polymethacrylate, guar gum, xanthan gum, carrageenan, castor oil, beeswax, carnauba wax, glycerol palmitostearate, glycerol monostearate, glycerol behenate, stearyl alcohol, and polyacrylic acid. Sustained-release agents may preferably be present in an amount of 5 to 70 wt.% with respect to the total weight of the composition.

[0037] The pharmaceutical composition may additionally contain a pharmaceutically acceptable component capable of forming carbon dioxide upon contact with gastric juices, and such component may preferably be selected from carbonates of alkali metals and alkaline earth metals and hydrogen carbonates; preferably, it may be present in an amount ranging from 1 to 50 wt.% of the total weight of the composition.

[0038] A typical daily dose of rebamipide for an average human (70 kg body weight) may be in the range of 1 to 5000 mg, more preferably 50 to 2500 mg, much more preferably 100 to 1000 mg, and most preferably 300 to 500 mg. When calculating the daily dose for human body weight, a typical dose range is 15 μg / kg / day to 70 mg / kg / day, more preferably 750 μg / kg / day to 35 mg / kg / day, even more preferably 1.5 mg / kg / day to 15 mg / kg / day, and most preferably 4 mg / kg / day to 7 mg / kg / day.

[0039] When an immediate-release formulation of rebamipide is administered, the daily dose is typically divided into several separately administered doses. The daily dose may be divided into 2 to 6 separate doses taken 2, 3, 4, 5, or 6 times a day. In a preferred embodiment, the daily dose is divided into three separate doses administered three times a day, for example, 100 mg doses administered three times a day. Alternatively, the entire daily dose may be taken at once, and particularly if it is in the form of a sustained-release formulation, for example, a 300 mg dose administered once a day. Specific details for implementing the invention

[0040] Examples of carrying out the present invention

[0041] A DSS model combined with PhIP treatment was used to investigate the effects of rebamipide on increased intestinal permeability, colon inflammation, and cancer development. Male CD-1 rats divided into three groups designated A through C were used in the study. Initially, rats in all groups received a single intragastric dose (200 mg / kg body weight) of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), a heterocyclic amine (HCA) present in cooked meat that is potentially carcinogenic. Subsequently, all rats were subjected to inflammatory stimulation using 2% sodium dextran sulfate (DSS) in drinking water for 7 days, followed by a recovery period of 2–4 weeks during which they were provided with untreated water. This cycle was repeated up to 4 times to increase intestinal permeability and induce severe colitis accompanied by body weight loss and bloody stools. Subsequently, multiple colon tumors developed in most of the rats.

[0042] Treatment with dextran sulfate sodium (DSS) induces inflammation and colitis by binding to medium-chain fatty acids present in the colon and increasing intestinal permeability. Furthermore, DSS administration causes the long-term development of dysplasia and even colon cancer in some treated mice. PhIP treatment accelerates this process and further increases the incidence of colon tumors. Another benefit of including PhIP in the protocol is that it reduces the dose of DSS in mice and decreases mortality rates due to DSS-associated acute colitis.

[0043] The carcinogenic process of the DSS / PhIP system involves pathological progression from normal intestinal crypts to the formation of lesions containing abnormal crypts accompanied by cryptic fissures, ultimately leading to the appearance of microadenomas. These stages summarize the sequence of colorectal cancer formation in humans, progressing from increased intestinal permeability and inflammation through dysplasia to carcinoma.

[0044] Rebamipide treatment was initiated 4 weeks prior to the administration of the carcinogen and continued throughout the study. Groups A and B received 50 mg / kg / day and 350 mg / kg / day of rebamipide, respectively. Rebamipide was administered within standard daily doses or via gastrointestinal feeding if necessary. Treatment lasted for 20 weeks. Rats in control group C did not receive rebamipide or other protective treatments.

[0045] Table 1: Overall Research Schedule

[0046] procedure Duration note Induction stage 4 weeks Rebamipide preliminary treatment 1 week PhIP single intragastric (ig) dose, 200 mg / body weight Exposure / Treatment Stage 15 weeks DSS (1 week) + recovery period (2 weeks), 4 cycles leading to increased intestinal permeability and colitis finish 1 week Sacrifice, Section, Post-mortem Analysis

[0047] The observed parameters are as follows:

[0048] o Number and size of tumors

[0049] o Histological evaluation of the tumor

[0050] o Weight loss

[0051] o Assessment of colitis severity

[0052] o Long-lasting permeability

[0053] o Cytokines and related markers (IL-6, IL-10, IL-1β, TNFα, iNOS, IL-23p19, MCP 1, MIP 2, CXCL1)

[0054] o Cell-cell adhesion proteins (Claudin 1, β-catenin)

[0055] o Expression of target genes

[0056] PhIP / DSS treatment caused rapid destruction of the colon mucosa accompanied by severe inflammation, followed by the development of colon adenocarcinoma. Interestingly, preliminary results from this study indicate a significant difference between the control group and the rebamipide treatment group. Mice in groups A and B recovered more quickly from DSS treatment, and the incidence and size of tumors were lower at the end of the study.

[0057] This is because rebamipide is known to induce cyclooxygenase-2 (COX-2) expression, which is known to be elevated in about 50% of colorectal adenomas and 85% of adenocarcinomas (Eberhart CE et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology . 1994;107(4):1183-8; Gupta RA and Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer . 2001;1(1):11-21; Marnett LJ and Dubois RN. COX-2: a target for colon cancer prevention. Annu Rev Pharmacol Toxicol. 2002;42:55-80), this is a surprising observation as it is associated with worse survival rates in CRC patients. Abnormal expression of COX-2 occurring in most colorectal tumors is thought to play an important role during the development of colorectal cancer.

[0058] The results obtained from this study show that the administration of rebamipide supports the regeneration of the intestinal barrier, thereby reducing the permeability of the gastrointestinal mucosa; consequently, it prevents the entry of carcinogens into the organism and suppresses intestinal inflammation, thus preventing or at least delaying the onset of symptoms and markers corresponding to colon cancer as a representative diet- and inflammation-related cancer compared to untreated animals.

Claims

Claim 1 A pharmaceutical composition comprising rebamipide, for use in the prevention of colon cancer in a person suffering from increased intestinal permeability. Claim 2 A pharmaceutical composition according to claim 1, wherein the person suffering from increased intestinal permeability is a person suffering from stress, an unbalanced diet, or a bacterial, viral, or parasitic infection. Claim 3 A pharmaceutical composition according to claim 1 or 2, wherein the person suffering from increased intestinal permeability is a person exposed to at least one substance selected from nonsteroidal anti-inflammatory drugs, alcohol, nicotine, food additives, chemotherapy drugs and antibiotics. Claim 4 A pharmaceutical composition according to paragraph 3, wherein the rebamipide is administered concurrently or sequentially with a non-steroidal anti-inflammatory drug, a chemotherapy agent, or an antibiotic. Claim 5 A pharmaceutical composition according to paragraph 3, wherein the rebamipide is administered to a person who abuses a drug selected from alcohol and nicotine. Claim 6 A pharmaceutical composition according to claim 1, wherein the person is a person suffering from at least one condition selected from stress-induced gastritis, digestive toxicity, cholinergic acid imbalance, gastric HCl and pepsin secretion, non-infectious diarrhea, radiation therapy, chemotherapy, infectious or post-infectious damage to the GIT mucosa, and dysmicrobia. Claim 7 A pharmaceutical composition according to claim 1, wherein the person suffering from the increased intestinal permeability is a person suffering from chronic intestinal inflammation including low-grade inflammation of the intestinal barrier. Claim 8 A pharmaceutical composition according to claim 1, wherein the person has a state in which colon cancer has a complete or partial remission after previous treatment. Claim 9 In claim 1, the pharmaceutical composition, wherein the person is in the early or early stage of colon cancer. Claim 10 A pharmaceutical composition according to claim 1, wherein the rebamipide is administered in the form of an oral drug selected from tablets, capsules, coated tablets, granules, microgranules (packets), orally dissolving tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, mouthwashes or rinses, or administered in the form of a rectal drug selected from suppositories and enemas. Claim 11 A pharmaceutical composition according to claim 10, wherein the oral formulation is an enteric-release type, an enteric-sustained-release type, or an enteric-controlled-release type. Claim 12 A pharmaceutical composition according to claim 10 or 11, wherein the pharmaceutical form comprises rebamipide and at least one pharmaceutically acceptable excipient selected from fillers, binders, lubricants, lubricants, disintegrants / swelling agents, solubilizers, enteric release agents, mucosal adhesive components, sustained release agents, preservatives, coating agents, and coloring agents. Claim 13 A pharmaceutical composition according to claim 1, wherein the rebamipide is administered at a daily dose of 1 to 5000 mg. Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete

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