WO2008047853A1

WO2008047853A1 - Prophylactic/therapeutic agent for gastroesophageal reflux disease

Info

Publication number: WO2008047853A1
Application number: PCT/JP2007/070313
Authority: WO
Inventors: Koji Takeuchi; Hisayuki Uneyama; Shinichi Fujita
Original assignee: Ajinomoto Co., Inc.
Priority date: 2006-10-19
Filing date: 2007-10-18
Publication date: 2008-04-24
Also published as: JPWO2008047853A1

Abstract

Disclosed are a more effective prophylactic/therapeutic agent for gastroesophageal reflux disease and others. Specifically disclosed are: a prophylactic/therapeutic agent for gastroesophageal reflux disease, which comprises glycine, arginine, or both of glycine and arginine as an active ingredient(s); and a composition for ameliorating gastroesophageal reflux disease, which comprises glycine, arginine, or both of glycine and arginine as an active ingredient(s).

Description

Specification

Gastroesophageal reflux disease prevention and treatment

Technical field

[0001] The present invention relates to a prophylactic / therapeutic agent for gastroesophageal reflux disease. The agent is used as a medicine, food and drink.

Background art

[0002] Gastro-esophageal reflux disease (GERD) is a gastro-esophageal reflux disease (GERD) that is caused by various gastrointestinal symptoms (heartburn) due to the reflux of gastric contents, duodenal juice, bile, phlegm and the like into the esophagus. , Oxalic acid, grip feeling, difficulty swallowing, chest pain, tingling, etc.). In particular, inflammation of the esophageal squamous epithelium is observed due to reflux of gastric acid and the like. Gastric esophageal reflux occurs even in healthy individuals. When the frequency increases, inflammation is caused by gastric acid, pepsin contained in the stomach contents, or duodenal juice. GERD includes gastroesophageal reflux esophagitis with organic changes observed by endoscopy and non-ulcer dyspepsia (non-ulcer deysp sia; NUD). Includes reflux conditions. In addition, even if endoscopic inflammation is not observed, inflammation may occur due to biopsy or the like, and even mild inflammation may cause subjective symptoms such as heartburn. In this case, it is assumed that sensory nerves are hypersensitive due to inflammation.

[0003] The incidence of GERD in Japan has increased rapidly since the 1970s when advanced industries developed and the sanitary environment improved and the Westernization of the diet progressed. Currently, it is more than 15% of upper gastrointestinal endoscopy The frequency has reached the same level as Europe and America. The reasons for this are the increase in gastric acid secretion capacity associated with the increase in fat and protein intake and the decrease in the infection rate of H. pylori bacteria. Of course, the current Asian countries will inevitably increase in the future. It has been. Furthermore, there is concern about further increase due to thorough sterilization therapy of H. pylori for the treatment and prevention of gastric and duodenal ulcers. Everybody has experienced stomach abdominal discomfort due to stomach upset, heartburn and stress after meals, and GERD can be said to be a disease that represents modern society along with lifestyle-related diseases. In addition, one of the features of this disease is a high recurrence rate, and stricture due to organic abnormalities due to relapses. It is desirable to prevent it by treatment.

[0004] Causes of GERD include gastric reflux (transient lower esopha geal sphincter relaxation; TLESR), resistance of esophageal mucosa to acid and / or pepsin Such as decreased esophageal clearance, decreased esophageal clearance after reflux, delayed gastric emptying, and esophageal hiatal hernia. Additional factors include increased gastric acid secretion due to dietary changes, increased food intake, and increased abdominal pressure due to obesity.

[0005] In addition, even in patients who have been unable to take orally due to mastication or dysphagia and have to rely on nutritional supplementation with gastric fistula, there is a clinical problem in preventing gastroesophageal reflux after treatment. It has become. In these patients, regurgitation of gastric contents is considered to be a major cause of aspiration pneumonia, which threatens patient life. In addition, some of these patients may not be able to complain of indefinite complaints for reasons such as language disorder or consciousness disorder, so that they can eliminate organic functional disorders and improve sensory disorders such as indefinite complaints. It is regarded as important in terms of improving QOL.

[0006] On the other hand, the incidence of food allergies in infants has tended to increase in recent years and has become an important problem in infant health. In these infants with food allergies or infants who may develop allergies, GERD is often accompanied by urgent early treatment (Non-patent Document 2). For example, in European pediatric GERD treatment guidelines, the use of high-viscosity milk is recommended as the first step of treatment (Non-patent Document 3). As other trials for treatment, the development of low antigenic milk powder and the development of milk for the purpose of suppressing backflow have been attempted (Non-patent Document 4; Patent Document 1).

[0007] Gastric acid secretion inhibitors such as proton pump inhibitors (PPI) and H2 antagonists, antacids, gastrointestinal motility improvers, and mucosal protective agents have been used for the treatment of GERD. Of these, gastric acid secretion inhibitors have been confirmed to have a clear healing effect. In particular, the cure rate for PPi is as high as 80% or more (Non-patent Document 5). However, long-term maintenance therapy for PPI is often required due to recurrence and aggravation due to the rebound phenomenon caused by withdrawal of medication. Moreover, when it is administered over a long period of time, its safety has not yet been determined, so it must be examined regularly. The pros and cons of PPI long-term administration for young people are being discussed. It is in. More recently, in some GERD patients undergoing PPI treatment, a reduction in the therapeutic effect due to the nocturnal acid breakthrough (“NAB”) that is restored at night is being clarified. Therefore, it is difficult to obtain a therapeutic effect with sufficient safety of these existing drugs, and there is a need for a completely new and conceptual therapeutic agent that can replace acid secretion suppression! /, The

[0008] In addition to the drugs listed above, drug development aimed at the prevention and treatment of GERD includes novel gammaaminobutyric acid (GABA) receptor agonists (Patent Document 2), thieno [3, 2— b] pyridine carboxamide derivatives (Patent Document 3), novel 5-HT4 agonist (Patent Document 4; Patent Document 5), smooth muscle modulator (Patent Document 6), nitrogen monoxide such as nitroglycerin and nitrate (hereinafter referred to as NO) Yes, free drugs are known! /, Ru (Non-patent Document 6). Receptors and NO-agonizing proteins that are the targets of these drugs are not limited to the esophagus and stomach, but are distributed in organs in the body, including the brain, and thus exert various physiological effects. For example, the 5-HT4 receptor is involved in motor control of the digestive tract, the GABA receptor is involved in brain neurotransmission, and NO is involved in blood pressure regulation in general. Of course, it is expected that it will be very difficult to clear both the high curative effect and safety in humans. In fact, new treatments are currently born from these new attempts. Les.

On the other hand, it has been reported that glutamine, which is an amino acid, has an effect of improving organic gastrointestinal diseases such as ulcers without causing side effects (Non-patent Document 7). Glutamine has been used as a treatment for gastritis-stomach 'duodenal ulcers, but it has been investigated for the action of gnoretamine on the squamous epithelium of the esophagus! Since arginine is also a precursor of NO, studies to verify the therapeutic effects of arginine on GERD have been conducted targeting the effects of lower esophageal sphincter (LES) modulation. However, arginine showed LES regulation by continuous intravenous infusion (Non-patent Document 8), but its effectiveness was not confirmed by oral administration of arginine (Non-patent Document 8). Reference 9). In addition, arginine is known to exhibit an antioxidant activity in vitro (Non-patent Document 10). It has been found to have an anti-inflammatory effect in vivo!

On the other hand, glycine is a force known to be abundantly contained in saliva. Until now, its physiological role in the mucous membrane of the digestive tract has been unknown. In recent years, a kind of macrophage The expression of glycine receptor is confirmed in upper cells, and as a new treatment method using glycine based on suppression of cell function of macrophage system, the use of glycine for liver damage prevention and treatment and transplantation of organs such as liver and kidney is expected. /! (Non-Patent Document 1 1; Non-Patent Document 12). However, at this stage, the involvement of macrophages in the pathogenesis of GERD is unclear, and glycine is not expected to be used for GERD prophylaxis. In addition, general anti-inflammatory drugs (such as non-steroidal anti-inflammatory drugs) are known to cause gastric mucosal damage and exacerbate GERD (Non-Patent Document 13). Even assuming that ginine and glycine have anti-inflammatory effects in vivo, it is difficult to analogize their use for GERD prophylaxis.

Until now, as described above, force S such as PPI and H2 receptor antagonist has been used as a treatment for gastroesophageal reflux. However, it has been reported that H2 receptor antagonists cannot sufficiently improve gastroesophageal reflux symptoms. Although PPI improves symptoms, it must be taken for a certain period of time to improve symptoms. It is not fast-acting, and it is not effective in severely ill patients due to insufficient suppression of acid secretion at night. In addition, there are many problems such as being sufficient, and if taking the medicine is stopped, it will recur immediately and easily worsen. In order to prevent recurrence, PPI must be taken for a long time, but the safety of long-term use has not been established.

Patent Document 1: Japanese Unexamined Patent Publication No. 2003-245039

Patent Document 2: Japanese Translation of Special Publication 2004-532259

Patent Document 3: International Publication No. 01/058898 Pamphlet

Patent Document 4: Japanese Translation of Special Publication 2002-521448

Patent Document 5: JP-T 8-502032

Patent Document 6: Special Table 2004—521898

Non-Patent Document 1: Dent J. Gut, Vol. 29, pl020_1028 (1988)

Non-Patent Document 2: Journal of Allergy and Clinical Immunology, Vol. 97, p822_827 (1996) Non-Patent Document 3: Acta Pediatrica, Vol.87, p462-468 (1998)

Non-Patent Document 4: Pediatric Internal Medicine, Vol. 26, 1994, p. 304-310

Non-Patent Document 5: Gastroenterology Vol.112, pl798_1810 (1997) Non-Patent Document 6: Curr Pharm Des., Vol.7 (l), pi-18 (2001)

Non-Patent Document 7: Nutrition., Vol.13 (7-8), p743_7 (1997)

Non-Patent Document 8: J Physiol Pharmacol., Vol.48 (2), p201_9 (1997)

Non-Patent Document 9: Am J Physiol., Vol.274 (6 Pt 1), pG984-91 (1998)

Non-Patent Document 10: Mol Pharmacol., Vol.61 (5), pl081_8 (2002)

Non-Patent Document 11: Curr Opin Clin Nutr Metab Care., Vol. 6 (2), p229-40 (2003) Non-Patent Document 12: Cell Mol Life Sci., Vol. 56 (9_10), p843- 56 (1999)

Non-Patent Document 13: Can J Gastroenterol., Vol. 19 (5), p 285-303 (2005)

Disclosure of the invention

Problems to be solved by the invention

[0012] An object of the present invention is to provide a novel preventive / therapeutic agent effective for the prevention and treatment of gastroesophageal reflux, which is a disease of the upper gastrointestinal tract.

Means for solving the problem

[0013] The present inventors have conducted intensive studies in order to solve the above problems, and that the composition containing glycine and / or arginine as an active ingredient has an action of preventing and treating gastroesophageal reflux disease. As a result, the present invention has been completed.

[0014] The present invention includes the following.

(1) A preventive / therapeutic agent for gastroesophageal reflux disease containing glycine, arginine, or glycine and arginine as active ingredients.

(2) The preventive / therapeutic agent according to (1) above, wherein the active ingredient is glycine and arginine, and the mass ratio of glycine to arginine is 1:10 to 10: 1.

(3) The prophylactic / therapeutic agent according to (1) or (2) above, wherein the daily dose of the active ingredient for an adult is lg to 20 g.

(4) A method for the prevention and treatment of gastroesophageal reflux disease, comprising administering glycine, arginine, or glycine and arginine as active ingredients.

(5) Use of glycine or arginine or glycine and arginine for producing a preventive / therapeutic agent for gastroesophageal reflux disease.

(6) Containing glycine or arginine or glycine and arginine for gastroesophageal reflux disease Food with a label indicating that it has an improving action and is used for the improvement of gastroesophageal reflux disease.

(7) The food according to (5) above, which contains glycine and arginine and has a mass ratio of glycine to arginine of 1:10 10: 1.

(8) The food according to (6) or (7) above, wherein the daily intake for an adult is lg 30 g as the total amount of amino acids.

(9) The food according to (6) or (8) above, wherein the food is a health functional food or a dietary supplement.

(10) The functional health food is specified health food or nutritional functional food.

(11) A composition for improving gastroesophageal reflux disease comprising glycine or arginine or glycine and arginine as active ingredients.

The invention's effect

[0015] The preventive / therapeutic agent for gastroesophageal reflux disease comprising glycine and / or arginine as an active ingredient provided by the present invention is used for preventing and / or treating gastroesophageal reflux disease. Since the prophylactic / therapeutic agent of the present invention contains amino acids as active ingredients, it is very safe as a pharmaceutical because it is highly safe and has few side effects.

In addition, since glycine and arginine, which are active ingredients in the preventive / therapeutic agent of the present invention, are substances having established safety, the prophylactic / therapeutic agent of the present invention is not limited to pharmaceutical use because of its high safety. It can be used for food.

Brief Description of Drawings

FIG. 1 is a diagram showing the inhibitory effect of glycine on acid reflux esophagitis. A: Effect of glycine on esophageal mucosal degeneration area. Control group N = 7, each glycine administration group N = 5; B: Typical case of esophagitis in rats administered with control mouth and glycine (250mg / kg, 375mg / kg, 750mg / kg)

FIG. 2 is a graph showing the inhibitory effect of arginine on acid reflux esophagitis. A: Effect of arginine on esophageal mucosal degeneration area. Control group N = 6, arginine administration group each N = 5; B: A typical example of esophagitis in control and arginine (250 mg / kg) administration rats. BEST MODE FOR CARRYING OUT THE INVENTION

[0017] The present invention provides a prophylactic / therapeutic agent for gastroesophageal reflux disease (hereinafter referred to as the prophylactic / therapeutic agent of the present invention). In the present invention, “prophylaxis” treatment means “improvement”. In the present invention, the term “agent” includes not only pharmaceutical preparations (pharmaceutical compositions) but also foods and drinks (food compositions).

[0018] In this specification, gastroesophageal reflux disease (GERD) refers to various gastrointestinal symptoms depending on the reflux of gastric contents, duodenal juice, bile, sputum, etc. into the esophagus and its stagnation. It is a general term for diseases that exhibit (heartburn, oxalic acid, feeling of gripping, difficulty swallowing, chest pain, tingling, etc.). Specifically, GERD includes reflux esophagitis, which shows an organic change by endoscopy, and non-ulcer dyspepsia (NUD), which has no endoscopic findings. ).

[0019] The prophylactic / therapeutic agent of the present invention improves gastroesophageal reflux disease (GER D) and gastrointestinal symptoms associated therewith. Specific symptoms of gastrointestinal symptoms that can be improved here include heartburn, oxalic acid, grip feeling, difficulty swallowing, chest pain, tingling, nausea, vomiting, aspiration, nausea, heartburn, fullness, Typical upper gastrointestinal complaints such as stomach upset, getp, chest distress, stomach discomfort, loss of appetite, lower gastrointestinal complaints such as abdominal pain, constipation, diarrhea and related complaints such as shortness of breath , Low motivation, laryngeal obstruction, foreign body sensation (“Ume-Kuki” in Chinese medicine), easy fatigue, stiff shoulders, tension, mouth irritations (blow, dry mouth), respiratory distress, extremity heat, cold sensation, concentration Examples include difficulty, frustration, sleep disturbance, headache, general malaise, palpitation, night sweats, anxiety, lightness, dizziness, heat, hot flashes, sweating, abdominal pain, constipation, and depression. In addition, the preventive / therapeutic agent of the present invention can be expected to have an effect of suppressing the reflux of stomach contents, duodenal juice, bile, sputum and the like into the esophagus, and an effect of recurring gastroesophageal reflux disease. .

[0020] Glycine and arginine, which are the active ingredients (amino acids) of the present invention, can be used in any of L-form, D-form, and DL-integral, but preferably L-integrated, DL-form, Preferably it is L-integral.

In addition, glycine and arginine can be used not only in a free form but also in a salt form, and the salt form is also included in the present invention. As salt form, with acid Salts and salts with bases can also be mentioned, and it is preferable to select glycine and arginine acceptable salts as pharmaceuticals! /.

Acids that form pharmaceutically acceptable salts when added to glycine and arginine, respectively, include, for example, inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; acetic acid, lactic acid, citrate, tartaric acid, Organic acids such as maleic acid, fumaric acid, monomethyl sulfuric acid and the like can be mentioned. Examples of pharmaceutically acceptable bases for glycine and arginine include, for example, metal hydroxides or carbonates such as sodium, potassium and calcium, or inorganic bases such as ammonia; ethylenediamine, propylenediamine, ethanol And organic bases such as amines, monoalkylenoethanolamines, dialkylethanolamines, diethanolamines, and triethanolamines.

[0021] As described above, in the present invention, gastroesophageal reflux is improved by administering an effective amount of the above-mentioned active ingredient to the administration subject. In this case, the active ingredient is used as it is or mixed with a pharmaceutical carrier. Taking into account the amount of active ingredient to be administered and the condition of the subject of administration (for example, patient), tablets (including sugar-coated tablets, film-coated tablets), pills, capsules, ampoules, and sachets , Elixirs, suspensions, syrups, gum preparations, drops preparations, powders, injections, suppositories, sustained release forms, ship-like forms, and pharmaceutical preparations such as coatings, orally or parenterally Can be administered. As an administration method, oral administration is preferred, and a sustained drug release form is preferred. Examples of sustained-release forms include conventional sustained-release agents such as gel-coated preparations and multiple-coated preparations, as well as gum preparations, drops preparations, stereotactic release agents (esophageal rupture preparations, pyloric rupture preparations, etc.) and the like. On the other hand, in order to improve symptoms quickly, a form showing rapid action is also preferable. Examples of the fast-acting form include a foaming agent. About the said dosage form etc., the same aspect can be taken also about foodstuffs.

[0022] Here, "administration subject" refers to individuals suffering from gastroesophageal reflux (for example, humans, domestic animals and poultry such as horses, horses, pigs, hidges, dogs, birds, mice, rats, etc.) The same applies hereinafter), and individuals that may suffer from the gastroesophageal reflux. The “effective amount” means an amount sufficient to give a desired improvement effect. The dose of the active ingredient varies depending on the sex, age, weight, diet, mode of administration, GERD symptoms, degree of risk of inducing GERD, symptoms of organic diseases of the digestive tract, etc. Adult (weight The daily dose of the active ingredient for (as 60 kg) is preferably in the range of !!-20 g, more preferably 2-20 g, even more preferably 2-10 g. When applied to mammals other than humans, the intake of the prophylactic / therapeutic agent of the present invention may be appropriately adjusted depending on the body weight or size of the animal. In addition, when the preventive / therapeutic agent of the present invention contains glycine and arginine as active ingredients, the mixing ratio of the two kinds of amino acids is usually 1 in terms of mass ratio as the form of free amino acids. : 10 to; 10: 1 range, preferably 1: 3 to 3: 1 range. Outside this range, it is difficult to obtain an effective action effect. Such doses can be administered once or in several divided doses. The administration time may be before, after, or between meals. The administration period is not particularly limited. In the present specification, unless otherwise stated, the mass of amino acids is calculated as the form of free amino acids.

[0023] The above-mentioned "pharmaceutical carrier" refers to a pharmaceutically acceptable substance that exhibits as little pharmaceutical activity as possible in the body. Pharmaceutical carriers when administered orally include binders such as gum tragacanth, gum arabic, corn starch, gelatin; excipients such as dicalcium phosphate; disintegrants such as caustic starch, potato starch, alginic acid; stearic acid Lubricants such as magnesium; sweeteners such as sucrose; pigments; fragrances such as orange flavors; solvents such as water, ethanol and glycerol; nutrients such as proteins, amino acids, vitamins, lipids, and genoles. Can do. In addition, as a pharmaceutical carrier, pharmaceutically acceptable antioxidants such as cystine, dartathione, ascorbic acid, sodium metasulfite and sodium bisulfite, and acids such as calcium carbonate, aluminum hydroxide gel and aluminum quinate. A Japanese-style medicine is mentioned.

[0024] The dosage forms and pharmaceutical carriers of the pharmaceutical preparations described above are well known to those skilled in the art, and are described in, for example, Reimingtons Pharmaceutical Science, ed. 16 (1980), Mack Publishing Company. And a pharmaceutical carrier can be used.

[0025] When calculating the dose (intake) of the amino acid that is the active ingredient of the present invention, the value is the value of the active ingredient of the drug used for the purpose of treatment or prevention of the disease targeted by the present invention. Since the above-mentioned calculation method is determined as the amount, it is different from this, for example, the amino acids taken or administered for the purpose of normal dietary life or for the treatment of another disease! /, Is not necessary to be included in the calculation. For example, it is not necessary to calculate by deducting the amount of amino acid per day taken from the normal diet from the daily dose of the active ingredient in the present invention.

[0026] When the prophylactic / therapeutic agent of the present invention contains glycine and arginine as active ingredients, each of glycine and arginine may be contained alone or in a single preparation. When separately formulated and administered, the administration route and dosage form may be the same or different, and the timing of administration of each may be simultaneous or different. It is determined as appropriate depending on the type and effect of the drug used in combination. That is, the medicament of the present invention may be a preparation containing glycine and arginine at the same time, or may be a combined preparation in which each is separately formulated and used together. It includes all these forms. In particular, an embodiment containing all glycine and arginine in the same preparation is preferable because it can be easily administered.

[0027] In the present invention, the "mass ratio" indicates the ratio of the mass of each component in the preparation. For example, when each active ingredient of glycine and arginine is included in one preparation, it is the ratio of the content as individual free amino acids, and each active ingredient can be used alone or in any combination. When included in the formulation, it is the ratio of the mass as free amino acids of each active ingredient included in each formulation.

[0028] In the present invention, the actual dose ratio is a ratio of a single dose or a daily dose of each active ingredient per administration subject (for example, a patient). For example, when each active ingredient of glycine and arginine is contained in one preparation and is administered to an administration subject, the mass ratio corresponds to the dose ratio. When each active ingredient is administered alone or in combination in multiple preparations, the ratio of the total amount of each active ingredient in each preparation administered once or daily corresponds to the mass ratio.

[0029] In the present invention, the preventive 'therapeutic agent for gastroesophageal reflux disease' comprising glycine and / or arginine as an active ingredient can be used or used for the treatment 'prevention of gastroesophageal reflux disease'. Commercial packages are also included, including statements stating what should be done.

[0030] In addition, the present invention is characterized in that it contains glycine and / or arginine, has an action of improving gastroesophageal reflux disease, and is used to improve gastroesophageal reflux disease Is provided (hereinafter referred to as the food of the present invention). [0031] The food of the present invention contains glycine and / or arginine. The content of glycine and / or arginine in the food of the present invention is usually 1 to 1 00% by weight the total amount of amino acids, preferably 10 to; 100 weight ^_0/0, more preferably 50 to; 100 weight ^_0/0, preferably 80 by further; 100% by weight. When the food of the present invention contains glycine and arginine, the mixing ratio of the two amino acids is usually in the range of 1: 100 to 100: 1, more preferably 1:10 to 10: 1, more preferably 1: 3 to 3: 1. Outside this range, it is difficult to obtain an effective action effect.

[0032] The "food" of the present invention may be any general food form containing glycine and / or arginine. For example, an appropriate flavor can be added to form a drink, for example, a soft drink or a powdered drink. Specifically, for example, it is possible to eat and drink by mixing glycine and / or arginine with juice, milk, confectionery, jelly, yogurt, candy and the like.

It is also possible to provide such foods as health functional foods or dietary supplements. This functional health food includes food for specified health use and functional food for nutrition. The food for specified health use is a food that can indicate that a specific health purpose can be expected, for example, improvement of gastroesophageal reflux disease. In the case of functional nutritional foods, the function of nutritional ingredients can be displayed if the amount of nutritional ingredients contained in the recommended daily intake meets the upper and lower limit standards set by the government. It is food. Dietary supplements include so-called nutritional supplements or health supplements. In the present invention, the food for specified health use is a food with a label indicating that it is used for applications such as improvement of gastroesophageal reflux disease, and further described that it is used for strength and use. This includes foods that contain the documents (V, narratives, etc.) Furthermore, the food of the present invention can be used as a concentrated liquid food or a food supplement. When used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like. The food supplement in the present invention refers to those ingested for the purpose of supplementing nutrition in addition to those ingested as food, and includes nutritional supplements and supplements.

[0033] In addition, "concentrated liquid food" means:! ~ Adjusted to a concentration of about 2 kcal / ml, long-term alone It is a comprehensive nutritional food (liquid food) that is designed based on daily nutritional requirements, taking into consideration the qualitative composition of each nutrient so that no significant excess or deficiency of nutrients occurs even when ingested.

[0034] When ingested as food, the amount of intake varies depending on the symptoms, age, weight, dosage form, method of intake, etc. of the subject. Adult (weight 60 kg) 1 g to 30 g as a whole amino acid per day Lg, preferably lg to 20 g, more preferably lg to about! Og. In the food of the present invention, the above-mentioned daily amount can be taken at one time or divided into several times. The amount of these intakes can be packaged in one unit. The intake period is not particularly limited.

[0035] In the present invention, the food containing glycine and / or arginine includes a document describing that it can or should be used to improve gastroesophageal reflux disease. Commercial packages are also included.

[0036] The contents of all publications, including patents and patent application specifications cited in this specification, are hereby incorporated by reference herein to the same extent as if all of them were explicitly stated. It is built in.

[0037] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples.

Example

[Example 1] Glycine and arginine prevent the development of esophagitis' therapeutic effect

(Experimental method) Male Sprague Dawley rats (200_230g; Charles River Japan) were used in the experiment. The model of acid reflux esophagitis is based on the simultaneous development of the pylorus and glandular stomach; see "Nagahama K, amamoto M, ato Ί uchiuchi; J. Pharmacol. ¾ci. 93; 55-61; 2003 Each amino acid (glycine, arginine) was dissolved or suspended in 0.5% carboxymethylcellulos (CMC-Na; Nacalai) and then administered intragastrically 10 minutes later (5 ml / kg, ig). The esophagus and stomach were removed, tissue fixed with 2% formalin aqueous solution, and a third party who was not informed of the experimental contents measured the area (mm ² ) of mucosal damage including hemorrhage in the esophagus. xlO) was measured under, and the effect of each amino acid was judged.

(Experimental result) Intragastric administration of glycine and arginine administered esophageal mucosa damage area It was suppressed in a dose-dependent manner (Figures 1 and 2).

Example 2 Effects of Glycine and Arginine on Gastric Fluid and Gastric Acid Secretion

(Experimental Method) An acid reflux esophagitis model was prepared in male SD rats by the same method as in Example 1. After 4 hours, the stomach was removed under ether anesthesia, the gastric fluid was collected, and after centrifugation (3000 rpm x lOmin), the pH of the supernatant was measured with a normal pH meter, and the volume was measured. Actual measurement was performed with a cylinder (10 ml). The total acid secretion was quantified with an automatic titrator (Commtite 550; Hiranuma Seisakusho) using lOOmM NaOH. Each amino acid (glycine, arginine) was dissolved or suspended in 0.5% carboxymethylcellulose (CMC-Na; Nacalai) and then administered intragastrically 10 minutes later (5 ml / kg, ig).

(Results) The results are shown in Table 1. Intragastric administration of glycine (750 mg / kg) resulted in gastric secretion, increased total acid secretion, and decreased gastric pH. Intragastric administration of arginine (250 mg / kg) lowered gastric fluid pH without significantly affecting gastric juice and total acid secretion. However, gastric fluid pH was not so large as to affect inflammation (Dig Dis Sci, 51, 303-309, 2006), and it became clear that simple suppression of gastric acid secretion could not be explained.

[0040] [Table 1]

(Table 1) Fl solution of glycine and arginine. Effects on total acid secretion and gastric fluid pH

Dos ^

Drugs No. of Volume Acidity Gastric

(mg / kg) rats (ml) (mEq 1) pH

Control 5 6.38 players 0.87 82.66 Sat 4.27 1,3 Sat 0,05

Glycine 750 4 8.63 players 0.41 110.89 Sat 3,86 * 2.31 »± 0.07 *

L-arginine 250 4 6.3 ± 0.18 88.56 Sat 3.2 1.82 ± 0.05 *

*: P 0. 001 v. S. Control group Industrial Applicability

[0041] The novel preventive / therapeutic agent for gastroesophageal reflux disease provided by the present invention can effectively prevent and improve gastroesophageal reflux, which has heretofore been difficult to prevent and treat. The active ingredient of the preventive / therapeutic agent for gastroesophageal reflux disease of the present invention should be applied to highly safe pharmaceuticals, foods, etc. It is extremely useful in industry.

This application is based on Japanese Patent Application No. 2006-285464 filed in Japan, the contents of which are hereby incorporated by reference.

Claims

The scope of the claims

[1] A preventive / therapeutic agent for gastroesophageal reflux disease containing glycine, arginine, or glycine and arginine as active ingredients.

[2] The active ingredient is glycine and arginine and the mass ratio of glycine to arginine is 1:10

The prophylactic / therapeutic agent according to claim 1, which is ˜10: 1.

[3] The prophylactic / therapeutic agent according to claim 1 or 2, wherein the daily dose of the active ingredient for an adult is lg to 20 g.

[4] A method for preventing and treating gastroesophageal reflux disease, comprising administering glycine, arginine, or glycine and arginine as active ingredients.

[5] Use of glycine or arginine or glycine and anoleginine for the manufacture of an agent for preventing or treating gastroesophageal reflux disease.

[6] A food for improving gastroesophageal reflux disease, comprising glycine and arginine and having a mass ratio of glycine to arginine of 1:10 to 10: 1.

[7] The daily intake for an adult is lg to 30 g as the total amount of amino acids.

4. The food described in 4.

[8] A composition for improving gastroesophageal reflux disease comprising glycine, arginine, or glycine and arginine as active ingredients.