JP5280415B2 - X-ray contrast medium contrast-improving agent, intestinal irrigation compound and intestinal irrigation kit - Google Patents

Description

  The present invention relates to a contrast enhancement agent for an X-ray contrast agent, more specifically, a contrast enhancement agent for an X-ray contrast agent for gastrointestinal tract examination, characterized by comprising a gastrointestinal motility promoter as an active ingredient, and an intestinal irrigation combination agent Intestinal lavage, and in addition to this, intestinal lavage combination, characterized by comprising gastrointestinal motility promoter as an active ingredient, and intestinal lavage kit, in detail intestinal lavage and in addition to gut motility The present invention relates to an intestinal tract cleaning kit or a packaged product characterized by using an accelerator.

  The benzamide derivative represented by the general formula described in Japanese Patent Publication No. 3-54937, “Claims”, No. 1 is known as a therapeutic agent for digestive tract diseases having a gastrointestinal motility function promoting action. Or as a gastrointestinal hypersensitivity agent, for the treatment and prevention of anorexia, nausea, vomiting, abdominal bloating, etc. It is a drug that can be used for the treatment and prevention of constipation. Among the various derivatives, citric acid of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide described in the same item 5 Salt (generic name: mosapride citrate) is marketed as a gastrointestinal motility promoter for the treatment of gastrointestinal symptoms (heartburn, nausea / vomiting) associated with chronic gastritis (trade name “Gasmotin”, Dainippon Manufactured by Pharmaceutical Co., Ltd.).

  As is well known, colorectal cancer is rapidly increasing in Japan with the westernization of meals, leading to colon cancer screening for the purpose of early detection, and colonoscopy and barium enema X-ray screening are screening. Or it is an inspection method indispensable for scrutiny. In addition, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease have also increased significantly, and the importance of these tests is rapidly increasing.

  Most of the large intestine diseases are caused by lesions that occur in the mucous membranes. In addition to finding the lesions, the enema X-ray examination and the colonoscopy are important means for grasping the characteristics of the fine lesions.

  Conventionally known enema X-ray examination methods are broadly divided into a filling method, a double contrast method, a compression method, and a mucous membrane method.

  Of these methods, enema double contrast is the most suitable for imaging and diagnosing lesions and occupies the main part of the current examination. Enema double contrast is a positive contrast agent that injects a contrast medium consisting of an aqueous barium sulfate suspension into the intestine and allows the contrast medium to reach the deep large intestine by changing the posture of the subject without draining it. By attaching barium sulfate as a thin layer to the inner wall of the large intestine, simultaneously injecting air as a negative contrast agent to inflate the large intestine, transmit X-rays, and draw the state of the large intestine mucosa on the X-ray film is there.

  In the enema X-ray examination, it is indispensable to perform a pretreatment for eliminating the contents of the intestinal tract, and the results of the enema X-ray examination are greatly influenced by the result of the pretreatment.

  Conventionally, a pretreatment method called a Brown modified method (Brown modified method) has been performed as a pretreatment for enema X-ray examination. This is a method of removing the contents of the large intestine by ingestion of a colon test meal consisting of a low-fat, low-fiber diet and administration of laxatives (salt laxatives such as magnesium citrate and contact laxatives such as picosulfate sodium), By this method, it is possible to depict the state of the mucosa of the large intestine as a fine mesh pattern (fine network pattern).

  However, in the modified Brownian method, there are not a few cases of poor pretreatment that cause residues in the intestinal tract and hinder the examination. This modified Brownian method has few problems with respect to the adherence of the contrast medium, but has to take an enema meal from the previous day, and also causes diarrhea due to a salt laxative, which places a heavy burden on the patient.

  As another method, there is a pretreatment method in which an intestinal cleanser (for example, trade name “NIFREC” (powder), manufactured by Ajinomoto Pharma Co., Ltd.) is dissolved in water, and this solution is orally administered to eliminate the intestinal contents. It has been adopted. However, in the pretreatment method using the intestinal rinsing agent, there are some cases where the contrast medium adheres to the intestinal mucosa and the fine network pattern is poorly drawn due to residual water in the intestinal tract.

  Thus, in the pretreatment method using only the intestinal tract cleaning agent, a good double contrast image cannot be obtained, and it is often difficult to depict a fine network pattern on the intestinal mucosa surface. In addition, since the dose of the intestinal irrigation water solution is large and the taste is not preferable, there are many patients who complain of nausea, abdominal pain and the like. On the other hand, the large intestine has a complicated three-dimensional structure, and considerable skill is required for an engineer so that the engraved contrast medium is sent to the deep part of the large intestine by body position change.

  Furthermore, in order for the contrast agent to adhere sufficiently to the intestinal wall, it is necessary to carry out detailed posture changes in various postures, in which case there are many burdens on physically handicapped patients and the elderly. It becomes.

  In view of the above, there is a demand for the development of a simple and highly acceptable pretreatment method and a drug used therefor, such as a digestive tract X-ray examination without impairing the imaging ability of the contrast agent and the need for dietary restriction on the day before the examination.

  In addition, in the colonoscopy, Koi et al. Have tried to reduce the dose of oral intestinal lavage fluid by combining oral intestinal lavage and mosapride citrate (Pharma Medica, vol.17, No.12). 1999, 132-133). In this report, residual bowels in the intestinal tract are observed at the time of colonoscopy, and the cleaning effect of the combined use of both agents is evaluated.

  However, in colonoscopy, since the inside of the intestinal tract is directly observed and diagnosed with an endoscope without using a contrast agent, the contrast agent when the pretreatment for enema X-ray examination is performed using both agents in combination. No knowledge about the imaging ability is described. Further, there is no description of a dosage form in the form of an intestinal tract cleaning compounded with both agents, or a dosage form in the form of an intestinal irrigation kit or package using both agents.

Pharma Medica, vol.17, No.12, 1999, 132-133

  The present invention eliminates the problems of diagnosis due to poor pretreatment for enema X-ray examination, improves the convenience of medication, and does not impose a burden on patients, particularly disabled patients and the elderly. An object is to provide an X-ray examination method and a pretreatment drug used therefor.

  As a result of various studies to achieve the object described in the preceding paragraph, the present inventors have improved the contrast-enhancing agent of the X-ray contrast agent for gastrointestinal examination that has solved the conventional drawbacks, and the X-ray image of the digestive tract. The present inventors have succeeded in providing a cleaning compound for intestinal tract cleaning in which both an imaging ability improving agent and an intestinal tract cleaning agent for enabling interpretation, and an intestinal cleaning kit or package using the same both.

  That is, the present inventors have found that the benzamide derivative represented by the general formula described in the above-mentioned Japanese Patent Publication No. 3-54937, “Claims”, is a sudden / chronic gastritis, gastric / duodenal ulcer, gastric nerve. Not only can it be used for the treatment and prevention of anorexia, nausea, vomiting, abdominal bloating, etc. in diseases such as sickness and gastric drooping, but also for the treatment and prevention of esophageal / biliary diseases and constipation, as well as barium sulfate, etc. They obtained the knowledge that the imaging ability of the X-ray contrast medium for gastrointestinal examination can be improved.

  More specifically, according to the benzamide derivative, the problem that hinders the adhesion of the intestinal mucosa to the contrast medium by the intestinal rinsing agent is solved, and an X-ray fluoroscopic image that can withstand diagnosis can be seen and a clear image can be obtained. It is possible to take images, and by using a kit that can administer the intestinal irrigant and the benzamide derivative simultaneously or non-simultaneously, the convenience of medication and administration can be increased, and attention to the side effects of patients can be raised, Furthermore, it has been found that such a kit contains medicines necessary for the treatment, and is useful for preventing medical errors due to drug mistakes, and the present invention is completed based on such knowledge. I reached.

  That is, the present invention relates to an imaging ability improving agent for an X-ray contrast agent for gastrointestinal tract, characterized by comprising a gastrointestinal motility promoter as an active ingredient, an intestinal irrigation agent, and a gastrointestinal motility promoter in addition to this The present invention relates to an intestinal lavage composition, characterized by comprising as an active ingredient, and an intestinal lavage kit and a packaged product characterized by using an intestinal lavage and a gastrointestinal motility promoter in addition thereto.

  Incidentally, the fact that the gastrointestinal motility promoting agent has the effect of improving the contrast performance of the X-ray contrast medium for gastrointestinal examination is that cisapride (Nippon Colorectal Society 16th No. 91-96) is used when “Nifurec” is used later. Except for page), it is not known conventionally.

  Hereinafter, the present invention will be described in detail.

Examples of the gastrointestinal motility promoter according to the present invention include benzamide derivatives, cisapride, metoclopramide and the like represented by the general formula described in the above-mentioned Japanese Patent Publication No. 3-54937 “Claims” including mosapride citrate. Serotonin 5-HT ₄ receptor agonists; dopamine D ₂ receptor blockers such as domperidone; acetylcholinesterase inhibitors / dopamine D ₂ receptor blockers such as itopride hydrochloride; and the like and the same pharmacological action as these compounds A compound can be mentioned (refer to the Japanese Pharmacology 113 , 299-307 (1999)). Among these compounds, mosapride citrate is considered to be most preferable in terms of few side effects such as induction of arrhythmia (Mosaprid and gastrointestinal motility issued in 1998 by Medical Review Co., Ltd.).

  The intestinal tract cleaning agent referred to in the present invention includes an isotonic agent and an electrolyte (without salt laxative) as main components, or magnesium citrate (Japanese Patent Laid-Open No. 5-306221), sodium dihydrogen phosphate, An example of a salt laxative such as disodium hydrogen phosphate prepared as an isotonic aqueous solution using an isotonic agent.

  Examples of isotonic agents include polyethylene glycol, particularly those having a molecular weight of about 4,000, water-soluble polymers such as dextran, dextrin, hydroxyethyl starch, polydextrose, gum arabic, carboxymethylcellulose, sodium alginate, and pectin. Kinds are available. Furthermore, saccharides such as trehalose, erythritol, xylitol, fructooligosaccharide, lactitol and maltitol can be used.

  Incidentally, as a specific example of the intestinal rinsing agent containing an isotonic agent and an electrolyte as main components, a composition comprising a combination of polyethylene glycol and an electrolyte (for example, related to the invention disclosed in JP-A-1-125319) The above-mentioned “Nifurec”), comprising a composition of a combination of at least one water-soluble polymer selected from dextran, dextrin, hydroxyethyl starch, polydextrose, gum arabic and pectin and an electrolyte (JP-A-2-25424) 3-206046), a composition composed of a combination of erythritol or xylitol and an electrolyte (JP-A-3-284620), or a composition composed of a combination of a fructooligosaccharide and an electrolyte (JP-A-3-291228). Gazette), and lactitol, maltitol and potassium Compositions containing at least one electrolyte selected from Bo carboxymethylcellulose (Japanese Unexamined Patent Publication No. 5-255092), and the like.

  The intestinal cleanser is formulated into a powder formulation (for example, the above-mentioned “NIFREC” relating to the invention described in JP-A-1-125319) or a tablet or granule dosage form in which each component is uniformly mixed in a powder form. May be. Furthermore, the form which filled the aluminum can, the flexible container, the rigid or semi-rigid container with the solution which melt | dissolved each component with water may be taken. At this time, the solution is of course sterilized or sterilized by a conventional method (Japanese Patent Laid-Open Nos. 9-58747, 8-253220, etc.).

  In addition, the usage-amount in this invention of a gastrointestinal motility promoter and an intestinal tract cleaning agent (intestinal tract washing | cleaning liquid) can apply to the usage-amount in each conventional use.

  The preparation of the intestinal tract cleaning composition of the present invention containing the above-mentioned gastrointestinal motility promoter and intestinal rinsing agent as active ingredients is not particularly limited in its preparation, and can be appropriately determined by conventional methods. In addition, this intestinal tract cleaning compound can be used not only for pretreatment for enema X-ray examination but also for pretreatment for colonoscopy.

  The intestinal tract cleaning kit or packaged product of the present invention is not particularly limited in its preparation, and can be appropriately determined by a conventional method. That is, it is only necessary to include a preparation containing at least both the aforementioned intestinal cleanser and gastrointestinal motility promoters such as mosapride citrate as active ingredients in one packaging form, and instructions describing the order of taking and the method of taking. It is preferable to put in a kit or packaged product, a cautionary statement that describes the symptoms that must be discontinued and the response to side effects. In addition, cups, dose check sheets, clocks, lysing solutions, etc. can be placed.

  As an example, a plastic container is filled with an intestinal irrigant (see Japanese Patent Application Laid-Open No. 4-259461), a mosapride citrate tablet and instructions for taking it, and symptoms of side effects and countermeasures are described. Removably install the blister pack containing the precautionary notes separately stored. And the form which inserts the said plastic container with a blister pack in the container of 2L capacity | capacitance for intestinal tract cleaning agent dissolution, or attaches it to an outer wall is useful. Convenience can be further enhanced by preliminarily filling the dissolution container with a solution such as mineral water.

  Moreover, you may attach the said blister pack to the container filled with the water solution of an intestinal tract cleaning agent.

  As another example, each of the drugs of the present invention (gastrointestinal motility promoter, intestinal rinsing agent, and dissolution solution) is divided into three compartments, which are also referred to as triple bags, and are divided by a fusion part. A good example is a kit bag that can accommodate three persons. This kit bag has a feature that it can be prepared by mixing the powdered intestinal cleanser and its solution by pressing the hand with the hand etc. during use and mixing the powdered intestinal cleanser and its solution. Yes. Then, if instructions and cautions are printed on the surface of the kit bag, it can be made into a kit with a single bag (Japanese Patent Application No. 2000-2619).

  In patients with inflammatory bowel disease, the contrast agent stimulates inflammation of the intestinal mucosa, and there is a concern about adverse effects on diseased parts such as ulcers, so the kit or package of the present invention contains a steroid agent for the purpose of preventing inflammation. May be included. Furthermore, sweeteners and flavoring agents may be added for the purpose of helping the intestinal cleaning agent. In particular, when polyethylene glycol is used as an isotonic agent, it is preferable to add a flavoring agent for the purpose of alleviating the bad taste.

  In addition, as long as the gastrointestinal motility promoter and the intestinal irrigant are used at the same time, they can be prepared in the form of an intestinal tract cleaning compound (composition) as long as the effect is obtained. If non-simultaneous administration is preferred, such as when taking the intestinal lavage fluid after administration, it may be in the form of a kit or package.

  Hereinafter, the present invention will be described in more detail with reference to test examples.

Test example 1
In order to investigate the contrast enhancement effect of contrast agent by mosapride citrate, dissolve one bag of oral intestinal irrigation agent (previously “Nifurec” (powder)) widely used in colonoscopy pretreatment in the past. 2L) and a tablet containing 5 mg of mosapride citrate (trade name “Gasmotin”, large) about 30 minutes before taking the oral intestinal detergent solution. Except for taking 3 tablets (Nippon Pharmaceutical Co., Ltd.) and taking the same pretreatment as in the control example, the adhesion of the contrast medium, the amount of residual water, and the fineness on the X-ray fluoroscopic image and the imaged film・ Compared the degree of rendering of network patterns.

  As a result, when mosapride citrate was administered, the amount of residual water was small despite the use of the same amount of intestinal lavage fluid, the adherence of the contrast agent to the intestinal mucosa was good, and the contrast ability of the contrast agent was sufficiently extracted. This makes it possible to draw a fine network pattern that was difficult in the past. Therefore, it was confirmed that mosapride citrate is useful as a contrast enhancement agent for contrast agents. As a result, it can be seen that the diagnosis of colorectal cancer and inflammatory bowel disease can be performed with high accuracy, in particular, where high fine network pattern visualization is required.

  Next, the effect of changing the timing of taking mosapride citrate in six colon examination examinees was confirmed (Test Examples 2 and 3).

Test example 2
When 7.5 mg of mosapride citrate was taken before and after taking an oral intestinal cleanser (previously “Nifurec” (powder) dissolved in water to make 2 L) (total amount of mosapride citrate taken in Test Example 1) 15 mg), the contrast agent adhesion in the left and right large intestine and the residual water in the large intestine were evaluated in 4 stages (4: good, 3: normal, 2: slightly bad, and 1: bad), respectively. (In this test example, mosapride citrate was divided into two total doses, 7.5 mg 30 minutes before the oral intestinal cleanser and 7.5 mg 30 minutes after the end of the dose. is there).

  Based on this evaluation record (data of 6 cases in the right and left large intestines), the adhesion rate of the contrast agent and the frequency% at which the evaluations at the respective stages 1 to 4 appear for both items of residual water are calculated. did. The results are shown in Tables 1 and 2 below.

Test example 3
When 15 mg of mosapride citrate was taken 30 minutes after the end of taking an oral intestinal cleansing agent (the above-mentioned “Nifurec” (powder) dissolved in water to make 2 L) (total amount of mosapride citrate taken is Test Example 1 The results of evaluation in the same manner as in Test Example 2 are shown in Tables 3 and 4 below.

  As described above, from Test Examples 1 to 3, the contrast enhancement effect of the contrast agent by mosapride citrate was obtained when mosapride citrate was dividedly administered before and after taking the oral intestinal cleanser, and before taking the oral intestinal cleanser or It was observed in all cases when administered after administration.

  According to the present invention, when a gastrointestinal motility promoter (contrast ability improving agent) is used in combination with the intestinal tract cleaner, residual water is reduced. In addition to the above, a clear fluoroscopic image is obtained, and the identified lesion site is targeted. Since the examination can be performed with a minimum number of scans, the patient's pain and the patient's X-ray exposure can be greatly reduced. In particular, it is possible to reduce the examination burden on the elderly.

  Furthermore, the use of the kit or package of the present invention increases prevention of medical errors, prevention of side effects, suppression of medical expenses due to early detection of colorectal cancer, and ease of administration.

  Note that the above-described effects can be obtained also when performing computer tomography (X-ray CT).

  The contrast-improving agent of the present invention increases the accuracy of colonoscopy and barium enema X-ray examinations, and reduces the burden on patient pretreatment and examination, thereby improving the patient's quality of life (QOL). To contribute. Furthermore, by making a kit, the convenience and safety of medication can be improved, and the burden on medical staff can be reduced.

Claims (1)

  An improvement agent in the pretreatment of barium enema X-ray contrast examination with an oral intestinal cleansing agent comprising mosapride citrate as an active ingredient, characterized in that mosapride citrate is administered after taking the oral intestinal cleansing agent Agent.