JP6764856B2 - Stomach volume reducer - Google Patents

Description

Reference of related application

The present application enjoys the benefit of the priority of Japanese Patent Application No. 2015-50583 (filed on March 13, 2015), which is a prior application in Japan, and the entire disclosure thereof is hereby cited by reference. Be part of.

The present invention relates to a gastric volume reducing agent containing one or more selected from glutamine, methionine and phenylalanine as an active ingredient.

Lifestyle-related diseases are diseases that develop or progress due to genetic factors (originally, predisposition to the disease, etc.) and lifestyle-related factors (overeating, drinking too much, lack of exercise, smoking, etc.). Here, lifestyle-related diseases include hypertension, hyperlipidemia, diabetes, and the like, and important factors thereof include obesity due to overeating, drinking too much, lack of exercise, and the like.

Diet and exercise therapies are known as treatments for obesity, but the reality is that these therapies do not have sufficiently effective effects.

Recently, a clinical study of about 800 subjects has shown that surgery is more effective than diet and exercise as a treatment for obesity. Specifically, when we analyzed 11 clinical studies of obese people as subjects, we found that gastric banding (binding) compared to weight loss methods without surgery (diet therapy, exercise therapy, behavior therapy, medication, etc.) ), Surgery such as gastric bypass and gastric resection have been shown to lose an average of 26 kg in two years (Non-Patent Document 1).

Further, in methods other than surgery, a method of suppressing appetite as a result of obtaining a feeling of fullness by absorbing water by dietary fiber and staying in the stomach has been reported (for example, Patent Document 1).

Special Table 2004-508310

Viktoria L Glloy et al, Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomized controlled trials, BMJ, 347, f5934 (2013)

We screened for materials that reduce gastric volume using a non-invasive screening method for the stomach, and found that the major amino acids with dietary experience, glutamine, methionine, and phenylalanine, were found in the stomach. It was found to be effective in reducing capacity.

Specifically, in an in vivo test using rats, a screening method characterized by forcibly placing a balloon in the stomach of an animal under anesthesia to increase the internal pressure of the stomach of the animal is used. There was. Since this test system is non-invasive to the stomach, it can be said to be closer to the physiological condition of the stomach.

Using this test system, we monitored the adaptive relaxation when amino acids were administered to stimulate gastric extension in animals, and glutamine, methionine, and phenylalanine adapted to the stimulation of gastric extension. It was found to suppress the relaxation of the fundus and / or the upper body of the stomach (when given a gastric extension stimulus). The present invention is based on the above findings.

An object of the present invention is to provide a gastric volume reducing agent that is safe and can be ingested for a long period of time.

Further, according to the present invention, the following inventions are provided.
[1] An agent for reducing gastric volume, which comprises one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine as an active ingredient.
[2] The agent according to the above [1], which suppresses relaxation of the fundus and / or the upper body of the stomach adapted to the stimulation of gastric extension.
[3] The agent according to the above [1] or [2], which does not promote gastric emptying.
[4] An agent for preventing, treating and / or ameliorating obesity, which comprises one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine as an active ingredient.
[5] The agent according to any one of the above [1] to [4], which is formulated so that the daily intake or dose of amino acids in humans is 0.2 to 5 g in terms of solid content of amino acids. ..
[6] The agent according to any one of the above [1] to [5], which comprises a single ingestion amount or a packaging unit form per dose.
[7] A method for reducing gastric volume, which comprises ingesting one or more amino acids selected from glutamine, methionine and phenylalanine.
[8] Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the production of gastric volume reducing agents.
[9] A method for preventing, treating and / or ameliorating obesity, which comprises administering one or more amino acids selected from glutamine, methionine and phenylalanine to mammals including humans who need them. ..
[10] Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the prevention, treatment and / or production of ameliorating agents for obesity.

According to the present invention, it is possible to provide a gastric volume reducing agent that is safe and can be ingested for a long period of time.

The outline of the barostat test of Example 1 is shown. An example of the time-dependent change in the internal pressure (Pressure) applied to the test device and the barostat bag, and the time-dependent change in the volume of the barostat bag is shown. The adaptive relaxation (% vs. control) when the internal pressure of the barostat back in Example 1 is 8 mmHg is shown. *: P <0.05 vs. Control group (Student's t-test)

The present inventors have found a novel screening method characterized by non-invasive placement of a gastric balloon in a non-human mammal. In this screening method, as shown in the test described later (Example 1), in an in vivo test using a non-human mammal such as a rat, a balloon is forcibly placed in the stomach of the animal under anesthesia and a test sample is used. It is characterized in that the relaxation of the fundus is evaluated by increasing the internal pressure of the stomach of the animal after administration of the animal to stimulate the stomach to stretch and monitoring Adaptive relaxation (adaptive relaxation). In the conventional screening method, a non-human mammal was opened, the stomach was incised, and a balloon was placed, so that it was invasive to the stomach and it was difficult to say that it reproduced the physiological situation. On the other hand, since this screening method is non-invasive to the stomach, it can be said that it is a test system closer to the physiological condition of the stomach. Here, "adaptive relaxation" (adaptive relaxation) refers to the reflex action of the stomach in which the fundus expands in response to an increase in the internal pressure of the stomach when food enters the stomach.

The present inventors screened 20 kinds of amino acids in the test described later (Example 1), and 3 kinds of amino acids (glutamine (Gln), methionine (Met) and phenylalanine (Phe)) were adapted to stimulate the extension of the stomach. It has been found that it suppresses the relaxation of the fundus and / or the upper body of the stomach (Forestomach). That is, we have found that glutamine, methionine and phenylalanine reversibly reduce gastric volume.

The gastric volume reducing agent of the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient. Alternatively, as an embodiment of the agent of the present invention, it may be an agent containing only one or more selected from glutamine, methionine and phenylalanine as an active ingredient, and one selected from glutamine, methionine and phenylalanine or It is also possible to exemplify an agent containing only two or more kinds.

In the present invention, "decrease in gastric volume" can be evaluated by indexing the relaxation of the fundus and / or the upper body of the stomach adapted to the stimulation of gastric extension (see Example 1). For example, in the screening system of Example 1, it can be determined that the gastric volume is reduced when the gastric distension is suppressed as compared with the gastric distension due to adaptive relaxation at the time of administration of the control sample. Specifically, in the screening system of Example 1, when the increased volume of the stomach due to adaptive relaxation was 80% or less (preferably 70% or less, more preferably 60% or less) of the increased volume at the time of administration of the control sample. In addition, it can be judged that the gastric capacity has been reduced.

The agent of the present invention can preferably be used to suppress the relaxation of the stomach, and more preferably to suppress the relaxation of the fundus and / or the upper body of the stomach adapted to the stimulation of gastric extension. it can. From another point of view, the agent of the present invention can be used to reduce gastric volume without promoting gastric emptying (while suppressing gastric emptying).

Glutamine is one of the essential amino acids, in which D-form and L-form are present. L-Glutamine Cas No. Is 56-85-9, and its aliases are (S) -2-amino-4-carbamoylbutanoic acid, glutamine, γ-glutamine, and L- (+)-glutamine. Gln and Q may be used as abbreviations for glutamine. Glutamine is freely soluble in formic acid, slightly soluble in water, and practically insoluble in ethanol (16th revised Japanese Pharmacopoeia). Glutamine is known to be contained in various ingredients and foods such as wheat protein, casein, soybeans, and pork.

Methionine is one of the essential amino acids, in which D-form and L-form are present. L-Methionine Cas No. Is 63-68-3, and its aliases are (S) -4- (methylthio) -2-aminobutyric acid, (S) -2-amino-4- (methylthio) butanoic acid, (S) -3. -Phenyl-2-aminopropionic acid, L- (-)-methionine. Met and M may be used as abbreviations for methionine. Methionine is freely soluble in formic acid, slightly soluble in water, soluble in dilute hydrochloric acid, and extremely sparingly soluble in ethanol (16th revised Japanese Pharmacopoeia). Methionine is known to be contained in various materials and foods such as casein, bonito and soybeans.

Phenylalanine is one of the essential amino acids, in which D and L forms are present. L-Phenylalanine Cas No. Is 63-91-2, and its aliases are (S) -α-aminobenzenepropanoic acid, (2S) -2-amino-3-phenylpropanoic acid, and (S) -3-phenyl-2-amino. Propionic acid, L-β-phenylalanine, L- (-)-phenylalanine. Ph, F may be used as an abbreviation for phenylalanine. Phenylalanine is easily soluble in formic acid, sparingly soluble in water, soluble in dilute hydrochloric acid, and practically insoluble in ethanol (16th revised Japanese Pharmacopoeia). Phenylalanine is known to be contained in various materials and foods such as various proteins.

In the present invention, glutamine, methionine and phenylalanine may be free bases or hydrates, and may be organic acids (acetic acid, tartaric acid, fatty acids, etc.), organic bases, inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). , Sulfuric acid, perchloric acid, etc.), and inorganic bases (potassium, sodium, zinc, etc.) may form salts. As glutamine, methionine and phenylalanine, either D-form or L-form may be used, but it is preferable to use L-form.

In the present invention, glutamine, methionine and phenylalanine can be obtained from materials and foods rich in glutamine, methionine and phenylalanine by squeezing, concentrating, purifying, crystallization or extracting with various solvents. As various solvents, water or commonly used solvents such as alcohols, hydrocarbons, organic acids, organic bases, inorganic acids, inorganic bases, supercritical fluids, etc. may be used alone or in combination of two or more. It is possible. It is also possible to use those produced by microorganisms. Then, it is also possible to use a chemically synthesized one.

The agent of the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, and is a composition in combination with other additive ingredients that are acceptable for food hygiene or pharmaceutically acceptable. It may be configured as. Therefore, the agent of the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, and further contains other additive ingredients that are acceptable for food hygiene or pharmaceutically acceptable. , A composition for reducing gastric volume, or a composition for the prevention, treatment and / or amelioration of diseases and symptoms (particularly obesity) described below. In this case, the composition is selected from glutamine, methionine and phenylalanine, which are effective amounts for reducing gastric volume or for preventing, treating and / or ameliorating diseases and symptoms (particularly obesity) described below. It contains one or more amino acids.

In the present invention, the other additive components are not particularly limited, and those that promote or do not inhibit the effect of the agent of the present invention can be preferentially used. Other additives of the invention include, for example, excipients, binders, disintegrants, lubricants, fragrances, solubilizers, suspending or coating agents and other formulation aids, vitamins, minerals, organics. Examples include acids, sugars, peptides, sweeteners, acidulants, emulsifiers or flavors.

In the present invention, the actual form is not particularly limited, and those that promote or do not inhibit the effect of the agent of the present invention can be preferentially used. Practical forms of the agents of the present invention include, for example, tablets, capsules, granules, powders, syrups, liquids, suspensions, drinks or supplements.

In the present invention, the blending amount of one or more selected from glutamine, methionine and phenylalanine varies depending on the dosage form, symptoms, body weight, use and the like, and is not particularly limited. However, if mentioned, glutamine, methionine and One or more amino acids selected from phenylalanine (in terms of solid content) with lower limit values of 0.1%, 0.2%, 0.5%, 0.8%, 1%, 2%, 5 %, 8%, and the upper limit can be set to 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 15%. In the present invention, "%" is "w / w%" unless otherwise specified.

In the present invention, the daily intake and dose of one or more amino acids selected from glutamine, methionine and phenylalanine vary depending on age, symptoms, weight, use and the like, and are not particularly limited. For example, one or more amino acids (in terms of solid content) selected from glutamine, methionine and phenylalanine, with lower limit values of 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, Alternatively, there is an example of ingesting or administering with 0.9 g and an upper limit set to 5 g, 4 g, 3 g, 2.5 g, 2 g, or 1.5 g. More specifically, one or two selected from glutamine, methionine and phenylalanine for reducing gastric volume or for the prevention, treatment and / or amelioration of diseases and symptoms (particularly obesity) described below. The daily intake and dose of the above amino acids (in terms of solid content) in humans can be 0.2 to 5 g, preferably 0.3 to 4.0 g, and more preferably 0.7 to 2. It is 0 g, particularly preferably 0.9 to 1.5 g.

For example, when 40 ml, 100 ml, 200 ml, 300 ml, 500 ml, and 1000 ml of the beverage (amino acid content: 0.5 w / v%) shown in Example 2 are ingested, the amino acids of the agent of the present invention are 0.2 g, 0.5 g, 1 g, and so on. It means that 1.5g, 2.5g and 5g were ingested.

For example, when 1, 2, 3, 5, 10 and 20 tablets (amino acid content: 200 mg / tablet, about 33 w / w%) shown in Example 3 are ingested, 0.2 g of the amino acid of the agent of the present invention, 0. It means that 4g, 0.6g, 1g, 2g and 4g were ingested.

For example, when the supplement shown in Example 4 (amino acid content: 300 mg / grain) is ingested 1, 2, 3, 5, 10 grains, the amino acids of the agent of the present invention are 0.3 g, 0.6 g, 0.9 g, 1. It means that 5g and 3g were ingested.

In addition, as a type of supplement shown in Example 4, when a supplement is produced by filling 300 mg of the amino acid of the agent of the present invention in a No. 1 capsule of 0.08 g, the amino acid content of the agent of the present invention in the supplement is about 79 w. / W%.

The agent of the present invention may be used at the same time as or before or after ingestion of a conventionally known composition, food or drink, drug or the like having a gastric volume reducing effect, or may be used in combination before or after the ingestion of the composition, food or drink, pharmaceuticals, etc. It may be used at the same time as treatments (bariatric surgery, balloon placement, etc.) or before and after those treatments. Specific examples include, but are not limited to, satiety central stimulants, dietary fiber, bariatric surgery, balloon placement and the like.

The agent of the present invention includes various foods and drinks (milk, soft drinks, processed milk, dairy drinks, fermented milk, lactic acid bacteria drinks, yogurt, cheese, bread, biscuits, crackers, pizza crusts, gummy, candy, baked goods, puddings. , Jelly, Bavaroa, milk powder, liquid foods, foods for the sick, nutritional foods, frozen foods, processed foods and other commercial foods) may be mixed and ingested. The form of these foods and drinks may be liquid, paste, gel, solid, powder or the like. In addition, various foods and drinks may be ingested by blending one or more selected from glutamine, methionine and phenylalanine, which are clearly higher in concentration than usual.

Water, proteins, peptides, amino acids, sugars, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, flavors and the like can be used as components of foods and drinks containing the agents of the present invention. , These are not particularly limited. Examples of proteins include full fat powder, defatted milk powder, partially defatted milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, whey protein hydrolyzate, α-casein, β-casein, κ- Examples include animal and vegetable proteins such as casein, β-lactoglobulin, α-lactoalbumin, lactoferrin, soybean protein, chicken egg protein, meat protein, decomposition products thereof, whey, non-protein nitrogen and the like. Further, examples of the peptide include casein phosphopeptide and the like.

Examples of carbohydrates include sugars, modified starches (in addition to textrin, soluble starches, British starch, oxidized starches, starch esters, starch ethers, etc.), dietary fiber and the like. Further, as lipids, for example, animal fats and oils such as lard, fish oil and ester exchange oil, palm oil, safflower oil, corn oil, rapeseed oil, coconut oil and the like, these fractionated oils, hydrogenated oils, ester exchange oils and the like. Examples include vegetable oils and fats. In addition, as vitamins, for example, vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, etc. Examples include choline and folic acid.

In addition, examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium and the like. Further, examples of the organic acid include malic acid, citric acid, lactic acid, tartaric acid, erythorbic acid and the like. The components of these foods and drinks can be used alone or in combination of two or more. It may also be a synthetic product and / or a natural product. The form of the components of these foods and drinks may be liquid, paste, gel, solid, powder or the like.

The agent of the present invention includes products such as health functional foods such as foods for specified health use, special purpose foods, nutritional functional foods, nutritional supplements, foods for the sick, health supplements, functional foods, non-pharmaceutical products or pharmaceuticals. Can be administered to a subject as provided as, or in combination with those products. In particular, the agent of the present invention may be provided as a health functional food such as a food for specified health use, a special purpose food, a nutritional functional food, a nutritional supplement, a food for the sick, a health supplement or a functional food. On the other hand, it is advantageous in reducing gastric capacity while clarifying the distinction from general (drinking) foods.

In the present invention, the foods listed above, foods for specified health use, foods with health claims, foods for special use, foods with nutritional claims, dietary supplements, foods for the sick, health supplements, functional foods, supplements, agents of the present invention. And one or more selected from glutamine, methionine and phenylalanine contained in one packaging unit of an agent consisting only of supplements for formulation, non-pharmaceutical products, or pharmaceuticals, glutamine, methionine. And can be set to 0.2 g, 0.3 g, 0.4 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, or 1 g, 1.5 g in terms of solid content of phenylalanine.

The agent of the present invention can be used not only in healthy subjects but also in persons with obesity, diabetes, hyperlipidemia, bulimia nervosa, polyphagia and other symptoms requiring dietary reduction before, at the same time as, or after eating or drinking. Ingestion can prevent, treat and / or ameliorate these diseases and symptoms. Alternatively, a person having another diet-saving disease or physical disorder (such as obesity) can prevent, treat and / or ameliorate these diseases and symptoms by taking the agent of the present invention. In particular, the agent of the present invention can reduce gastric volume without promoting gastric emptying, and as described in the background art column, it can reduce gastric volume as a treatment method (weight loss) for obesity. Is so effective that the agents of the present invention can efficiently prevent, treat and / or ameliorate obesity.

The present invention is also the use (method of use) of one or more selected from glutamine, methionine and phenylalanine for producing a gastric volume reducing agent. The present invention is also the use (method of use) of one or more selected from glutamine, methionine and phenylalanine for the production of obesity prevention, treatment and / or ameliorating agents.

The present invention is also a method for reducing gastric volume, which comprises using one or more selected from glutamine, methionine and phenylalanine for oral ingestion. The present invention is also a method for preventing, treating and / or ameliorating obesity, which comprises using one or more selected from glutamine, methionine and phenylalanine for oral ingestion or oral administration. In the above two methods, medical practice for humans may be excluded.

The present invention is also a method of reducing gastric volume, characterized in that one or more selected from glutamine, methionine and phenylalanine are orally ingested (commercially provided). The present invention also comprises orally ingesting one or more selected from glutamine, methionine and phenylalanine (commercially provided), a method for preventing, treating and / or ameliorating obesity. , But also. In the above two methods, medical practice for humans may be excluded.

The present invention is also a composition for reducing gastric volume, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient. The present invention is also a composition for preventing, treating and / or ameliorating obesity, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient.

The present invention is a beverage or drink for reducing gastric volume, which comprises one or more selected from glutamine, methionine and phenylalanine as an active ingredient and contains other additive ingredients acceptable for food hygiene. But also. In addition, the present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, and contains other additive ingredients acceptable for food hygiene, for the prevention, treatment and / or of obesity. It is also a beverage and drink for improvement. Other food hygiene-acceptable additive components that can be used in the beverages and drinks include food additives such as sweeteners and acidulants.

The present invention contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, contains other additive ingredients acceptable for food hygiene, and contains a formulation aid, gastric volume. It is also a supplement such as tablets for reducing methionine. In addition, obesity prevention, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient, contains other additive ingredients acceptable for food hygiene, and contains a formulation aid. It is also a supplement such as a tablet for treatment and / or improvement. Other food hygiene-acceptable additives that can be used in the supplements include food additives such as sweeteners, acidulants, emulsifiers, and flavors. Examples of formulation aids that can be used in the above supplements include any one or more of excipients, binders, disintegrants, and lubricants.

The present invention is also a supplement such as a capsule for reducing gastric volume, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient and contains a formulation aid. It is also a supplement such as a capsule for the prevention, treatment and / or amelioration of obesity, which contains one or more selected from glutamine, methionine and phenylalanine as an active ingredient and contains a formulation aid. Examples of formulation aids that can be used in the above supplements include any one or more of excipients, binders, disintegrants, and lubricants.

According to a preferred embodiment of the present invention
A fundus and / or upper body relaxation inhibitor adapted for gastric extension stimulation, which contains one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine as active ingredients.
Suppresses relaxation of the bottom and / or upper body of the stomach adapted to gastric extension stimulation, which involves ingesting one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine. Of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the method and the production of anti-relaxation agents in the bottom and / or body of the stomach adapted to the stimulation of gastric extension. Use is provided. The above invention can be carried out in accordance with the description of the gastric volume reducing agent of the present invention, the prophylactic, therapeutic and / or ameliorating agent of various diseases and symptoms, and the amino acids of the agent of the present invention.

According to the present invention, the following invention is provided.
[21] An agent for reducing gastric volume, which contains one or more selected from glutamine, methionine, and phenylalanine as an active ingredient.
[22] The agent according to the above [21], which suppresses relaxation of the bottom of the stomach and / or the upper part of the gastric body adapted to the stimulation of gastric extension.
[23] The agent according to the above [21] or [22], which does not promote gastric emptying.
[24] The agent according to any one of the above [21] to [23], wherein the daily intake of a human is 0.2 to 5 g.
[25] An obesity-preventing and / or ameliorating agent containing the agent according to any one of the above [21] to [23] as an active ingredient.
[26] A method for reducing gastric volume (excluding medical practice for humans), which comprises using one or more selected from glutamine, methionine, and phenylalanine for oral ingestion.
[27] A method for reducing gastric volume (excluding medical practice for humans), which comprises ingesting one or more selected from glutamine, methionine, and phenylalanine.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1: Test of gastric volume reduction effect on various amino acids (1) Materials and methods [Test sample]
19 kinds of amino acids (L-Phenyl alane (Phe), L-Lycine (Lys), Glycine (Gly), L-Cysteine (Cys), L-Serine (Ser), L-Alanine, L-Proline (Pro), L-Arginine (Arg), L-Histidine (His), L-Threone, L-Valine, L-Glutamine, L-Aspargine (Asn), L-Mestionine, L-Glutamic acid, L-Aspartic L-Isoleucine, L-Leucine, and L-Tyrosine) were used as test samples.

Among the above amino acids, hydrochloride was used for Lys, monohydrate was used for Asn, and free base was used for other amino acids. Each of these amino acids was dissolved and suspended in water for injection (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 1 g / 5 ml.

[Positive control sample]
As a positive control, Rikkunshito (Tsumura Rikkunshito extract granules (medical use), Tsumura), which is a Chinese herbal medicine used to improve stomach upset, was dissolved and suspended in water for injection (Otsuka Pharmaceutical) at a concentration of 500 mg / 5 ml. Used.
[Barostat bag]
A barostat bag in which two polyvinyl tubes were connected to a polyethylene bag (maximum capacity: 7 ml, maximum diameter: 3 cm) was used.

[Animal experimentation]
Uchida et al (Masayuki UCHIDA, Kimiko SHIMIZU, "Method to evaluate adaptive relaxation of the stomach by using Barostat in rats without surgical operation, and the effects of capsaicin and Nω-nitro-L-arginine-methylester on adaptive relaxation." J. Smooth Muscle Res., (2012) 48 (4)) was referred to.

That is, 8-week-old male SD rats (SLC) were preliminarily bred for 1 week and used for the test. On the day before the test start date, the animals were grouped based on body weight (20 groups in total, n = 4 to 8 animals each) and fasted for 18 to 20 hours (however, water was taken freely).
In the test sample administration group, 5 ml / kg of the above-mentioned dissolution / suspension of various amino acids (dose of the test sample: 1 g / kg), in the Control group, 5 ml / kg of water for injection, in the positive control group, Rikkunshito The solution / suspension of hot water was forcibly ingested at 5 ml / kg (Rikkunshito dose 500 mg / kg).

20 minutes after administration of the test sample or water for injection, anesthesia with urethane (20% urethane, 6 ml / kg, intraperitoneal administration) is performed, and 25 minutes after administration of the test sample or water for injection, a barostat bag is orally administered. It was inserted into the stomach. With one tube closed, 7 ml of air was injected into the barostat bag from the other tube, and the barostat bag was adjusted to be located from the fundus to the upper body of the stomach. After that, the barostat bag was promptly deflated.

Thirty minutes after administration of the test sample or water for injection, the barostat bag was inflated and the internal pressure and volume of the barostat bag were measured by connecting to a barostat device (Barostat Disaster IIR, G & J Electronics) and holding breathing. .. Specifically, the internal pressure of the barostat bag was set to 0 mmHg at the initial value, and the internal pressure was gradually increased to stimulate the extension from the fundus to the upper body of the stomach.

The internal pressure of the barostat bag at 0 to 1 minute, 1 to 2 minutes, 2 to 3 minutes, and 3 to 4 minutes after the start of measurement is set to 1 mmHg, 2 mmHg, 4 mmHg, and 8 mmHg, and the capacity of the barostat bag is continuously set. Was measured (Fig. 1).

After the measurement was completed, the abdomen was incised with the barostat bag inflated, and the stomach was observed to check the insertion condition (position, etc.) of the barostat bag, the bulging condition of the barostat bag, and the presence or absence of bleeding. ..

[Evaluation]
The volume (ml) of the barostat bag increased while maintaining the internal pressure of the barostat bag at each stage in about 1 minute was calculated, and this was taken as Adaptive relaxation (ml) (FIG. 1). Furthermore, the value obtained at each internal pressure was divided by the value of the control group to calculate adaptive relaxation (% vs. control group).

(2) Results Fig. 2 shows the adaptive relaxation when the internal pressure of the barostat back is 8 mmHg. In both the Gln group and the Met group, the values were significantly lower than those in the Control group. In the Ph group, the contraction action from the fundus to the upper body of the stomach strongly occurred, and the barostat bag was pushed out from the fundus to the upper body of the stomach and moved to the body of the stomach. In this phenomenon, Ph has been shown to have a stronger effect than Gln and Met.

From this, it was found that Gln, Met, and Phe suppress the relaxation of the fundus and / or the upper body of the stomach adapted to the stimulation of gastric extension, and reversibly reduce the gastric volume.

Example 2: Method for producing a beverage containing the agent of the present invention L-glutamine is 0.5 w / v%, sweetener 1.0 w / v%, acidulant 0.9 w / v%, and thickener 0.2 w. Beverages were prepared according to conventional methods by blending at a concentration of / v%. When 40 ml, 100 ml, 200 ml, 300 ml, 500 ml, and 1000 ml of this beverage are ingested, 0.2 g, 0.5 g, 1 g, 1.5 g, 2.5 g, and 5 g of L-glutamine can be ingested.

Similarly, a beverage containing 0.5 w / v% of L-methionine, a beverage containing 0.5 w / v% of L-phenylalanine, 0.2 w / v% of L-glutamine and 0.1 w / v of L-methionine. A beverage containing 0.2 w / v% of L-phenylalanine and a beverage containing 0.1 w / v% of L-glutamine and 0.4 w / v% of L-phenylalanine were produced.

Example 3: Method for producing a tablet containing the agent of the present invention A conventional method in which 200 mg of L-glutamine is mixed with an excipient, a binder, a disintegrant, a lubricant, an acidulant, an emulsifier, a fragrance, and a sweetener. According to this, about 600 mg of tablets were produced (L-aspartic acid content: about 33 w / w%). When these tablets 1, 2, 3, 5, 10 and 20 are ingested, 0.2 g, 0.4 g, 0.6 g, 1 g, 2 g and 4 g of L-glutamine can be ingested.

Similarly, a tablet containing 200 mg of L-methionine, a tablet containing 200 mg of L-phenylalanine, a tablet containing 50 mg of L-glutamine, 50 mg of L-methionine and 100 mg of L-phenylalanine, and 100 mg of L-methionine and L- A tablet containing 100 mg of phenylalanine was produced.

Example 4: Method for producing a supplement containing the agent of the present invention An excipient or the like was added to 300 mg of L-glutamine and filled into capsules to produce a supplement. By ingesting 1, 2, 3, 5, and 10 tablets of this supplement, 0.3 g, 0.6 g, 0.9 g, 1.5 g, and 3 g of L-glutamine can be ingested.

Similarly, a supplement filled with 300 mg of L-methionine, a supplement filled with 300 mg of L-phenylalanine, a supplement filled with 50 mg of L-glutamine, 100 mg of L-methionine and 150 mg of L-phenylalanine, and 200 mg of L-glutamine and L- A supplement filled with 100 mg of methionine was produced.

Claims (6)

An agent for reducing gastric volume, which comprises one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine as an active ingredient. The agent according to claim 1, which suppresses the relaxation of the fundus and / or the upper body of the stomach adapted to the stimulation of gastric extension. The agent according to claim 1 or 2, characterized in that it does not promote gastric emptying. The agent according to any one of claims 1 to 3, which is formulated so that the daily intake or dose of amino acids in humans is 0.2 to 5 g in terms of solid content of amino acids. The agent according to any one of claims 1 to 4, which comprises a packaging unit form per ingestion or dose. Use of one or more amino acids selected from the group consisting of glutamine, methionine and phenylalanine for the production of gastric volume reducing agents.

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