| JP2007056013 | SUPPLEMENTARY LIQUID FOR DIALYSIS |
| WO/2001/018202 | FLINT ANALOG COMPOUNDS AND FORMULATIONS THEREOF |
| WO/2007/144057 | ANTIMICROBIAL CARBON |
JUNG, Hyeon Sik (202 Hyeongje House, 1-10 Jongam 2-dong, Seongbuk-gu, Seoul 136-858, KR)
OH, Eui Chaul (109-903, Doosan Weve Apt.192, Geumgok-dong, Bundang-g, Seongnam-si Gyeonggi-do 463-850, KR)
CHOI, Eun Young (9-201, Hyundai Mansion605-4, Sinsa-dong, Gangnam-gu, Seoul 135-894, KR)
HAHM, Ki Baik (255-2, Seohyeon-dong Bundang-g, Seongnam-si Gyeonggi-do 463-824, KR)
JUNG, Hyeon Sik (202 Hyeongje House, 1-10 Jongam 2-dong, Seongbuk-gu, Seoul 136-858, KR)
OH, Eui Chaul (109-903, Doosan Weve Apt.192, Geumgok-dong, Bundang-g, Seongnam-si Gyeonggi-do 463-850, KR)
CHOI, Eun Young (9-201, Hyundai Mansion605-4, Sinsa-dong, Gangnam-gu, Seoul 135-894, KR)
| Claims [Claim 1] A pharmaceutical composition for the prevention or treatment of NSAID-induced enteropathy, comprising zinc acexamate. [Claim 2] The pharmaceutical composition according to claim 1, wherein the NSAID-induced enteropathy is small intestinal damage induced by NSAID. [Claim 3] The pharmaceutical composition according to claim 1 or 2, wherein the composition comprises a pharmaceutically acceptable carrier. [Claim 4] The pharmaceutical composition according to claim 1, wherein the composition further comprises any known prophylactic or therapeutic agent for NSAID-induced enteropathy. [Claim 5] A method for preventing or treating NSAID-induced enteropathy administering the pharmaceutical composition of claim 1. |
Title of Invention: A PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING NSAID-INDUCED ENTEROPATHY COMPRISING ZINC ACEXAMATE
Technical Field
[1] The present invention relates to the use of zinc acexamate for the prevention and treatment of NSAID (non-steroidal anti-inflammatory drug)-induced enteropathy, more particularly, to a composition for the prevention or treatment of NSAID-induced enteropathy comprising zinc acexamate and a method for preventing or treating NSAID- induced enteropathy by administration of the composition. Background Art
[2] There are disclosed therapeutic uses of zinc acexamate, such as treatment of gastro- duodenal ulcer (ES 2009266) and prevention of non-steroidal anti- inflammatory drug- induced gastropathy (EP 0369088 Bl, US patent No. 5,135,925). Practically, it was demonstrated that zinc acexamate showed the efficacy for the treatment of peptic ulcer in both in vitro and human studies, and also a high healing rate and a low recurrence rate (Jimenez E et al. Meta-analysis of efficacy of zinc acexamate in peptic ulcer. Digestion. 1992; 51(l):18-26. Escolar G et al. Zinc compounds, a new treatment in peptic ulcer. Drugs Exp Clin Res. 1989; 15(2):83-9.). In the prevention of nonsteroidal anti-inflammatory drug-induced gastropathy, zinc acexamate has also shown gastroprotective effect in both in vivo model and human (Bulbena O et al. Gastro- protective effect of zinc acexamate against damage induced by nonsteroidal antiinflammatory drugs. A morphological study. Dig Dis Sci. 1993; 38(4):730-9. Rodriguez de Ia Serna A et al. Multicenter clinical trial of zinc acexamate in the prevention of nonsteroidal anti-inflammatory drug induced gastroenteropathy. J Rheumatol. 1994; 21(5):927-33.). Further, the use of zinc acexamate in inflammatory bowel disease is disclosed in Korean Patent Publication No. 10-2006-42885. However, the etiology of inflammatory bowel disease has not yet been clarified and it is different from NSAID-induced enteropathy. As disclosed in Korean Patent Publication No. 10-2006-42885, it has been also demonstrated that the protective effects on NSAID- induced disease is not related to inflammatory bowel disease. Furthermore, zinc acexamate is also known to have effects on the treatment of gastroduodenal ulcer and the prevention of NSAID-induced gastropathy, but there is no report describing the effects of zinc acexamate on NSAID-induced enteropathy, in particular, small intestinal enteropathy.
[3] [4] Meanwhile, non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used in the treatment of various diseases. However, it has been widely known that NSAIDs directly cause mucosal damage due to their acidic properties, and inhibit the production of mucosal prostaglandins, leading to gastroenteropathy. For the prevention or treatment of NSAID-induced gastroenteropathy, a variety of therapeutic agents (Mucosta®, Stillen®, Gastrex®, and Cytotec®, etc.) have been developed. Practically, theses agents do not show significant effects on NSAID-induced enteropathy, whereas they show significant effects on NSAID-induced gastropathy. Misoprostol has only been used as a protective agent. Many studies have mainly focused on gastropathy. Recently, diagnosis of enteropathy has become easier, and the incidence rate is also increasing. In addition, NSAIDs are widely used, although they cause a wide range of side effects. In view of this, it is very important and urgent to develop agents for the prevention and treatment of NSAID-induced enteropathy. Disclosure of Invention Technical Problem
[5] In this viewpoint, the present inventors discovered that zinc acexamate has excellent effects of preventing and treating NSAID-induced enteropathy, in particular, small intestinal enteropathy, thereby completing the present invention. Solution to Problem
[6] It is an object of the present invention to provide a composition for the prevention or treatment of NSAID-induced enteropathy, comprising zinc acexamate.
[7] It is another object of the present invention to provide a method for preventing or treating NSAID-induced enteropathy by administration of the composition.
Advantageous Effects of Invention
[8] The composition according to the present invention significantly ameliorates
NSAID-induced enteropathy, in particular, small intestinal enteropathy including intestinal damage, an increase in intestinal permeability, and inflammation induced by NSAID, and also has more excellent protective effect than misoprostol, which is the only known agent to prevent the disease. Brief Description of Drawings
[9] FIG. 1 is a photograph of gastropathy, after administration of the known mucosal protective agents and zinc acexamate of the present invention. From FIG. 1, it cannot be expected that the prophylactic agents against gastropathy have the effects of treating or preventing enteropathy.
[10] FIG. 2 is a photograph of enteropathy, after administration of the known mucosal protective agents and zinc acexamate of the present invention.
[11] FIG. 3 shows a gross index of enteropathy, after administration of the known mucosal protective agents as prophylactic agents to prevent NSAID-induced enteropathy and zinc acexamate of the present invention.
[12] FIG. 4 is a table showing intestinal permeability measured by 51 Cr-EDTA excretion.
[13] FIG. 5 is scoring criteria for small intestinal enteropathy.
[14] FIG. 6 is the result of measuring a pathological lesion index on the basis of the scoring criteria in FIG. 5.
[15] FIG. 7 is the result of histological observation of intestinal permeability in the small intestinal epithelium. Best Mode for Carrying out the Invention
[16] In one embodiment, to achieve the above objects, the present invention relates to a composition for the prevention or treatment of NSAID-induced enteropathy, comprising zinc acexamate.
[17]
[18] NSAID is a therapeutic agent that represents anti-inflammatory effect through inhibition action of cyclooxygenase without steroid. It is presumed that about 30 million people around the world daily dose the NSAID for the purpose of anti- inflammatory, pain, fever. NSAID based on a variety of chemical structures can be categorized variously, but it can cause the common side effects, tipically, such as aspirin, diclofenac, etodolac, ibuprofen, celecoxib or the like.
[19]
[20] As used herein, the term "NSAID-induced enteropathy (or disease)" means all of
NSAID, namely, non-steroidal anti-inflammatory drug-induced diseases, and examples thereof include, but are not limited to, intestinal striction, ulceration, perforation, diarrhea, and villous atrophy, as disclosed in the literature by Kwo PY, et al. (Mayo Clin. Proc. 1995 70 (1):55-61). Preferably, the disease is NSAID-induced small intestinal enteropathy.
[21]
[22] The composition according to the present invention is characterized in that it comprises zinc acexamate as an active ingredient. Zinc acexamate used in the composition of the present invention is a derivative of N-acetyl-6-aminohexanoic acid, and can be easily prepared by the known method, or is commercially available. The known preparation method of zinc acexamate is to react zinc oxide with N- acetyl-6-aminohexanoic acid in polar solvent, which is described in detail in ES 2009266, but is not limited thereto. The salt separated by the method is a crystalline powder which is suitable for the preparation of pharmaceutical compositions. It is preferable that zinc acexamate is included in the composition of the present invention in an amount of 5 to 1000 mg in order to prevent or treat NSAID-induced enteropathy. [23]
[24] In the preferred embodiment, the composition according to the present invention may include pharmaceutically acceptable carriers in addition to the active ingredient, zinc acexamate. For oral administration, the pharmaceutically acceptable carriers may include a binder, a lubricant, a disintegrating agent, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a coloring agent, a flavor or the like. For injectable formulation, the pharmaceutically acceptable carriers may include a buffering agent, a preserving agent, an analgesic, a solubilizer, an isotonic agent, a stabilizer, and the mixture thereof. For preparations for topical administration, the pharmaceutically acceptable carrier may include a base, an excipient, a lubricant, a preserving agent or the like.
[25] The pharmaceutical composition of the present invention may be formulated into various preparations in conjunction with the above-mentioned pharmaceutically acceptable carriers. For oral administration, the pharmaceutical composition may be formulated into tablets, troches, capsules, elixirs, suspensions, syrups, wafers or the like. For injectable preparations, the pharmaceutical composition may be presented in unit dosage form, e.g., in ampules or in multi-dose containers. The pharmaceutical composition may be also formulated into solutions, suspensions, tablets, pills, capsules, sustained-release formulations or the like.
[26] Meanwhile, examples of suitable carriers, excipients, and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starches, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. The formulations may additionally include fillers, anti- agglutinating agents, lubricating agents, wetting agents, flavoring agents, preserving agent or the like.
[27] In another embodiment, the composition according to the present invention may further include a known prophylactic or therapeutic agent for NSAID-induced enteropathy, in addition to zinc acexamate.
[28] The composition according to the present invention significantly ameliorates
NSAID-induced enteropathy, in particular, small intestinal enteropathy including intestinal damage induced by NSAID, an increase in intestinal permeability, and inflammation, and also has more desirable effects than misoprostol, which is the only known agent to prevent the disease, as described in the following example. On the other hand, the mucosal protective agents used in clinical practice did not show significant protective effects on NSAID-induced small intestinal enteropathy.
[29] In still another embodiment, the present invention relates to a method for preventing or treating NSAID-induced enteropathy using zinc acexamate. In the preferred em- bodiment, NSAID-induced enteropathy can be prevented or treated by administration of the composition comprising zinc acexamate of the present invention.
[30] As used herein, the term "administration" means the introduction of a predetermined material into patients using a suitable method. As long as it guarantees the transmission of the administered material to a targeted tissue, any administration route may be taken. For example, the composition of the present invention may be administered in- traperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, locally, intranasally, intrapulmonarily, or intrarectally, but is not limited thereto. Preferably, the composition of the present invention may be administered orally or intrarectally. Also, zinc acexamate or the pharmaceutical composition comprising the same may be administered with the aid of a device for guiding the active material to a targeted cell.
[31] The dose of zinc acexamate or the pharmaceutical composition comprising the same may vary depending on various factors, including the kind of disease, administration route, the age, sex, and body weight of patients, severity of disease, and the kind of active ingredient.
[32]
[33] Hereinafter, the present invention will be described in more detail with reference to the following example. However, the present invention is not intended to be limited by the following example. Mode for the Invention
[34] Example 1. Prophylactic and therapeutic effects of zinc acexamate on NSAID- induced enteropathy in rat
[35]
[36] The efficacy of zinc acexamate on NSAID-induced enteropathy (small intestine) was demonstrated in animal model.
[37] Sprague-Dawley rats (20Og - 25Og) were used as an animal model, and the active ingredient of the present invention, zinc acexamate and other known therapeutic drugs for NSAID-induced enteropathy were used to compare their activities. As the therapeutic drugs for NSAID-induced enteropathy, Cytotec (Cytotec®, misoprostol), Mucosta (Mucosta®, rebamipide), Stillen (Stillen®, Artemisiae argyi folium ethanol ext) and Gastrex (Gastrex®, ecabet sodium) were used. Indomethacin, the most frequently used NSAID, was used to induce enteropathy. As a control group, rats were administered with NSAID only. All of the drugs, NSAID, and 51 Cr-EDTA were given by post oral administration. On day 1 and 2, the drugs were administered, and after 1 hr, NSAID (15 mg/kg) was administered. After 4 hr, the rats were supplied with feed. This procedure was performed for two days to induce NSAID damage. On days 3 and 4, the rats were administered with only the drug without fasting. The last drug was administered on day 5, and after fasting for 10 hrs, 51 Cr-EDTA lOuCi (suspended in 2 ml of saline) was administered. After administration of 51 Cr-EDTA, each rat was transferred to a metabolic cage, and the urine was collected for 16 hrs. Then, a laparotomy was performed to observe organ damage. The organ damage was shown in FIGs. 2 to 4. 51 Cr-EDTA excretion in 100 ul of urine was measured using a γ counter. Pathological specimens of the small intestines of the subject animals were made to assess pathological lesion index on the basis of scoring criteria. As a result, the protective effect of zinc acexamate was demonstrated, which corresponds to the gross observations. From the viewpoint of pharmacological action, NSAID administration induces changes in small intestinal permeability, which be attributed to the reduction of ZO-I or occludin in the small intestinal epithelium (Musch MW et al., Roles of ZO- 1, occludin, and actin in oxidant-induced barrier disruption. Am J Physiol Gastrointest Liver Physiol. 2006; 290(2):G222-G231). Confocal microscopy was performed to observe localization of ZO-I or occludin in the small intestine of the subject animal. As a result, the significant protective effect was observed only in the zinc acexamate- treated group even after NSAID administration, not in the mucosal protective agent- treated groups. This result revealed that zinc acexamate has more excellent protective effect than misoprostol, and thus plays an important role in the prevention of NSAID- induced damage to the intestinal epithelium.
[38] As shown in FIGs. 2 to 4, and FIGs. 6 to 7, zinc acexamate significantly ameliorates the side effects of ascites, peritonitis, and enteritis due to indomethacin administration in a dose-dependent manner, and has more excellent protective effect than misoprostol, which is the only known agent to prevent NSAID-induced enteropathy. As compared to other mucosal protective agents used in clinical practice, zinc acexamate showed much higher efficacy for the prevention or treatment of NSAID-induced enteropathy. Industrial Applicability
[39] The composition according to the present invention significantly ameliorates
NSAID-induced enteropathy, in particular, small intestinal enteropathy, and also has more desirable effects than misoprostol, which is the only known agent to prevent the disease, as described in the following Example. On the other hand, the mucosal protective agents used in clinical practice did not show protective effects on NSAID- induced small intestinal enteropathy (see FIG. 1). Recently, NSAIDs have been widely used in the treatment of various diseases, and the increased life expectancy accelerates the use of NSAIDs. In addition, in the United States, gastrointestinal system complications due to NSAID are serious enough to die as many as 16,500 people annually. Thus, zinc acexamate according to the present invention is industrially applicable for the prevention and treatmentof NSAID-induced side effects.
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