JPWO2017002765A1 - Calorie reducing composition - Google Patents

Abstract

A calorie reducing composition containing a cyclic dipeptide or a salt thereof, and a food or drink comprising the calorie reducing composition. The composition for reducing calorie of the present invention is mainly absorbed as a conjugate of a water-soluble molecule such as unchanged substance or glucuronic acid without the cyclic dipeptide contained therein being efficiently absorbed in the living body and being decomposed into free amino acids. Since it is excreted as it is, it is useful for, for example, diet, calorie reduction, or prevention and / or improvement of metabolic syndrome.

Description

  The present invention relates to a composition for reducing calories. More specifically, the present invention relates to a calorie reducing composition containing a cyclic dipeptide as an active ingredient, a low calorie composition containing the cyclic dipeptide, and a method for producing the same.

  In recent years, with the westernization of eating habits, obesity due to excessive intake of calories and various diseases associated therewith have become a problem, and the development of materials that can be used for the purpose of reducing intake calories is desired. ing.

  For example, Patent Document 1 is obtained by mechanically stirring a gelatinized product obtained by adding more than 0.5 times the amount of water to rice containing high amylose rice and / or medium amylose rice and heat-treating it. It is disclosed that the rice gel can be used as an alternative food material or an alternative food for diet or calorie reduction by substituting part or all of protein, oil and fat, and grains other than rice originally contained in the food material or food.

  On the other hand, “dipeptides” in which two amino acids are bonded are attracting attention as functional substances. Dipeptides can add physical properties and new functions not found in simple amino acids, and are expected to have a range of applications beyond amino acids. Among these, diketopiperazine, which is a cyclic dipeptide, is known to have various physiological activities, and various studies have been conducted.

  For example, Patent Document 2 discloses that by heating an aqueous solution containing at least one of a linear dipeptide and a linear tripeptide containing at least one proline or hydroxyproline as a constituent, at least one proline or It is disclosed that a cyclic dipeptide containing hydroxyproline as a constituent can be easily produced. Specifically, for example, cyclo (Gly-Pro) is efficiently produced by heat treatment (90 ° C., 24 hours) of a linear dipeptide, glycylproline (Gly-Pro) in an aqueous solution ( Conversion rate 92.6%).

WO2014 / 199961 Japanese Patent No. 545676

  However, it is not yet known whether cyclic dipeptides can be used as a material for reducing calories.

  The subject of this invention is providing the raw material for calorie reduction which uses cyclic dipeptide as an active ingredient, the composition for calorie reduction containing this cyclic dipeptide, and its manufacturing method.

The present invention relates to the following [1] to [6].
[1] A calorie reducing composition containing a cyclic dipeptide or a salt thereof.
[2] A food or drink comprising the calorie reducing composition according to [1].
[3] A method for producing a food or drink comprising using the calorie reducing composition according to [1].
[4] A method for reducing calories of the composition, which comprises blending a cyclic dipeptide or a salt thereof with the composition.
[5] Use of a cyclic dipeptide or a salt thereof for reducing the calories of the composition.
[6] A method for reducing caloric intake, comprising a step of administering an effective amount of a cyclic dipeptide or a salt thereof to an individual who needs to reduce caloric intake.

  The composition for reducing calories of the present invention has an excellent effect that it can be used as a material for reducing calories, and a composition containing this is effective for dieting.

  The present invention is characterized by using a cyclic dipeptide in order to reduce calorie intake. One reason why such an effect is exhibited is thought to be due to the characteristic that the cyclic peptide is excellent in permeability from the intestinal tract and is not easily degraded by peptidases and the like. Since cyclic dipeptides have two amino acid terminal moieties linked via an amide bond (ie, cyclic dipeptides have a cyclic structure formed by the amide bond between the amino terminus and the carboxy terminus) Therefore, the lipophilicity is higher than that of a linear dipeptide (particularly, a linear dipeptide having the same kind of amino acid composition) in which a carboxy group or amino group, which is a polar group, is exposed at the molecular terminal portion. Therefore, the cyclic dipeptide is excellent in gastrointestinal permeability, membrane permeability, and hence absorption, as compared with a linear dipeptide. This is also clear from the results of a compound permeation test using a rat inverted intestinal tract reported in the past (J. Pharmacol, 1998, 50: 167-172). In addition, cyclic dipeptides are less susceptible to peptidases in the body than linear peptides due to their cyclic structure, and therefore are not decomposed into free amino acids after absorption from the digestive tract. As a result, it is considered that the cyclic dipeptide is not used for protein synthesis, but is excreted outside the body mainly as an unchanged form or a conjugate of a water-soluble molecule such as glucuronic acid, and does not serve as an energy source. However, these assumptions do not limit the present invention. Utilizing the characteristics of such cyclic dipeptides, providing foods and drinks with reduced calories while satisfying fullness and satisfaction after ingestion by replacing some of the nutrients in the foods and drinks with cyclic dipeptides Is possible. Moreover, about the functional food etc. which paid its attention to the effect of cyclic dipeptide, it becomes possible to provide the food / beverage products with the added value of being a low calorie in addition to the effect effect which a cyclic dipeptide has.

  The calorie reducing material of the present invention is a calorie reducing composition containing a cyclic dipeptide or a salt thereof as an active ingredient. Hereinafter, the calorie reducing material of the present invention is also referred to as a calorie reducing composition. Moreover, the cyclic dipeptide or its salt used in order to reduce intake calories may be collectively described as the cyclic dipeptide of the present invention.

  Examples of the cyclic dipeptide of the present invention include cycloglycylproline [Cyclo (Gly-Pro)], cycloprolylhydroxyproline [Cyclo (Pro-Hyp)], cyclohydroxyprolylglycine [Cyclo (Hyp-Gly)]. Cyclovalylserine [Cyclo (Val-Ser)], Cycloarginylglycine [Cyclo (Arg-Gly)], Cycloalanylvaline [Cyclo (Ala-Val)], Cycloglutaminylserine [Cyclo (Gln-Ser)] And the like. You may use these individually by 1 type or in combination of 2 or more types. Especially, the case where a cyclic dipeptide contains a glycine and / or proline as a structural element can be mentioned as a suitable example. In the present specification, as long as the amino acid structure in the cyclic dipeptide is the same, any of the description order thereof may be first, for example, Cyclo (Gly-Pro) and Cyclo (Pro-Gly) are the same cyclic dipeptide. That is.

  In the present specification, the salt of the cyclic dipeptide refers to any pharmacologically acceptable salt of the cyclic dipeptide (including inorganic salts and organic salts), for example, sodium salt, potassium salt of the cyclic dipeptide, Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate, Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, etc.).

  The cyclic dipeptide of the present invention can be prepared according to a method known in the art, and commercially available products can also be used. For example, it may be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or may be synthesized by dehydrating and cyclizing a linear peptide. For example, a heat-treated product obtained by heat-treating plant components and / or animal components can be suitably used.

  The plant component used in the present invention is not particularly limited as long as it contains a linear dipeptide, tripeptide, or oligopeptide. Specifically, for example, one or more plant extracts selected from the group consisting of soybean, malt, barley, wheat, coffee, black beans, sesame, and tea can be mentioned. As the extraction method, a known method can be used, and extraction may be performed so as to include the above-described linear peptide. Moreover, a commercial item can be used.

  The animal component used in the present invention is not particularly limited as long as it contains a linear dipeptide, tripeptide, or oligopeptide. Specific examples include one or more selected from the group consisting of collagen peptides, milk, whey, casein, and placenta extract. These origin animals are not particularly limited. These animal components may be prepared according to known techniques, or commercially available products may be used.

  Examples of the heat treatment method of the plant component and / or animal component include a method of heating the plant component and / or animal component in a solution or in a solid phase.

  Examples of the solution medium used in the heat treatment include water, an organic solvent, and a mixture thereof. Examples of the organic solvent include ethanol and hexane. The mixing ratio in the case of mixing with water is not particularly limited.

  The pH of the solution at the time of the heat treatment and the concentration of the raw material used for heating are not particularly limited, and can be appropriately set according to the type of medium as long as heating is possible.

  The heating temperature is not set unconditionally depending on the type of raw material or medium to be heated, but 100 to 170 ° C. is exemplified in both heating in solution and heating in the solid phase. 110-150 degreeC is preferable. The heating time can be appropriately set depending on the heating temperature, and examples thereof include 0.25 to 10 hours.

  For example, in the case of cycloglycylproline [Cyclo (Gly-Pro)], after preparing a collagen peptide containing the linear dipeptide Gly-Pro in an aqueous solution of an arbitrary concentration, A material containing Cyclo (Gly-Pro) is obtained by heating at ˜170 ° C. for about 0.25 to 10 hours.

  Thus, a calorie reducing material containing the cyclic dipeptide of the present invention is obtained.

  Other ingredients are not particularly limited as long as the calorie reducing material of the present invention contains the cyclic dipeptide or a salt thereof. For example, when the material is a solid material, the content of cyclic dipide or a salt thereof in the dry solid is not generally set depending on the raw material to be heated, but is 0.01% (w / w)% or more It is preferable that it is 0.1 w / w% or more. For example, for Cyclo (Gly-Pro), the content in soybean is 0.02 to 0.30 w / w%, the content in barley malt is 0.01 to 0.20 w / w%, the content in tea The amount is 0.02 to 0.30 w / w%, and the content of collagen peptide is about 1.0 to 30 w / w%. In addition, content of cyclic dipetide or its salt can be measured by the HPLC method, for example.

  In addition, when the material is a liquid material, the content of the cyclic dipeptide or its salt per Brix in the liquid is not set unconditionally depending on the raw material used for heating, but is preferably 1.0 ppm / Brix or more. More preferably, it is 10 ppm / Brix or more. For example, for Cyclo (Gly-Pro), the content in soybean is 2.0-30 ppm / Brix, the content in barley malt is 1.0-20 ppm / Brix, and the content in tea is 2.0- The content of 30 ppm / Brix and collagen peptide is about 100 to 3000 ppm / Brix. In this specification, “amount per Brix” means an amount determined by a value corresponding to a mass percentage of a sucrose solution at 20 ° C. (an aqueous solution containing only sucrose as a solute). Unless otherwise specified, “ppm” used herein means ppm of weight / volume (w / v), and 1.0 ppm / Brix is 0.1 mg / wt when the specific gravity of the solvent is 1. Converted to mL and converted to 0.01% by weight. In addition, content of cyclic dipetide or its salt per Brix can be measured using HPLC or a saccharimeter, for example.

  In the calorie reducing material of the present invention, the cyclic dipeptide from which the cyclic dipeptide or its salt is eliminated suppresses metabolism by peptidase in the living body. Therefore, when the ingested cyclic dipeptide is 100 wt%, at least 35 % By weight, preferably 50% by weight or more, more preferably 90% by weight or more is excreted in the urine as an unchanged form or a conjugate of a water-soluble molecule such as glucuronic acid. The upper limit is not set and may be 100% by weight or less.

  In addition, with respect to the calorie reducing material of the present invention obtained, one or more treatments selected from the group consisting of filtration, centrifugation, concentration, ultrafiltration, lyophilization, pulverization, and fractionation. May be prepared according to a known method, or may be formulated as it is, or may be prepared in a form that can be used for raw materials such as pharmaceuticals, quasi drugs, and foods and drinks. Therefore, the said processed material is contained as one aspect | mode of the raw material for calorie reduction of this invention.

  The present invention also provides a composition containing the calorie reducing material of the present invention, that is, the calorie reducing composition of the present invention. By including the calorie reducing material of the present invention in the composition, the composition can be suitably used as a low calorie composition. Hereinafter, the composition may be simply referred to as the composition of the present invention. Therefore, such a composition is an embodiment of the calorie reducing material of the present invention, and a composition containing a cyclic dipeptide or a salt thereof is included in the present invention. In the present specification, the low calorie is preferably less than 5 kcal / 100 mL (100 g in the case of solid matter), more preferably less than 4 kcal / 100 mL (100 g in the case of solid matter), and more preferably 3 kcal / 100 mL (solid matter). Means less than 100 g). Here, the number of calories is basically a value calculated according to “Analysis method of nutritional components and the like in nutrition labeling standards” published in relation to the health promotion method.

  The low-calorie composition of the present invention can be suitably used for the purpose of reducing caloric intake or dieting, or for diseases that require a caloric intake-reducing action, for example, pharmaceuticals, quasi drugs, or foods and beverages It is used as a form of Therefore, as a mode of the low calorie composition of the present invention, a pharmaceutical, a quasi drug, or a food or drink can be mentioned.

  In the present invention, the disease requiring the action of reducing caloric intake is not particularly limited as long as it has a therapeutic effect by reducing caloric intake. Examples include diabetes, hypertension, obesity, hyperuricemia, dyslipidemia, arteriosclerosis and the like.

  Moreover, since the calorie intake is suppressed by containing the cyclic dipeptide of the present invention or a salt thereof, the composition of the present invention is extremely useful for symptom improvement and prevention of diseases requiring a caloric intake reduction action. That is, the composition of the present invention can be used as a food for specified health use, a nutritional functional food, a special-purpose food, a functional indication food, a health supplement (supplement), for example, for the purpose of preventing or ameliorating the above-mentioned diseases. , Diet, calorie reduction, or the indication that it is used for prevention and / or improvement of metabolic syndrome. It is a very useful composition for those who are concerned about blood pressure, those who are concerned about blood pressure, those who are concerned about blood sugar after meals, those who are concerned about uric acid level, and the like.

  In addition, the composition of the present invention is not limited to a composition mainly intended to reduce calories, but feels hunger and stress due to dietary restrictions by replacing some of the components with the calorie reducing material of the present invention. Therefore, it is possible to achieve prevention or amelioration of the above diseases while obtaining a feeling of fullness after eating.

  The content of the cyclic dipeptide of the present invention or a salt thereof in the composition of the present invention cannot be set unconditionally depending on the type of cyclic dipeptide, its preparation conditions, post-treatment conditions, etc., from the viewpoint of exerting its effects Preferably, it is 0.01 w / w% or more, More preferably, it is 0.1 w / w% or more, More preferably, it is 1.0 w / w% or more. Also, the upper limit is not particularly set, and as an alternative component such as dipeptides, tripeptides, oligopeptides, proteins, lipids, carbohydrates, etc. can do. By substituting in this way, degradation to amino acids in the body is suppressed, and it is excreted in the urine mainly as an unchanged form or a conjugate of a water-soluble molecule such as glucuronic acid, which corresponds to the conventional component Calorie intake can be suppressed.

  The composition of the present invention can be appropriately contained as a component other than the cyclic dipeptide of the present invention or a salt thereof as long as the effects of the present invention are not impaired. Moreover, it is also possible to improve the stability and added value of the composition by using other useful components in combination. Their content is not particularly limited as long as it does not impair the effects of the present invention.

  The composition of the present invention may be prepared according to a known production method by mixing the raw material for calorie reduction of the present invention with its raw materials when preparing a known pharmaceutical product, quasi-drug, or food or drink. Moreover, you may prepare by adding the raw material for calorie reduction of this invention to a well-known well-known food-drink, and melt | dissolving and / or suspending. In addition, a well-known pharmaceutical, a quasi-drug, or food-drinks may contain the said cyclic dipeptide or its salt originally, and it mixes and prepares suitably in the range with the effect of this invention. can do.

  The form of the composition of the present invention is not particularly limited. For example, carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks (including fruit juices), fruit drinks, fruit foods with fruit grains, vegetable drinks, soy milk, Soy milk beverages, coffee beverages, tea beverages, jelly beverages, powdered beverages, concentrated beverages, sports beverages, nutritional beverages, alcoholic beverages and other favorite beverages, nutritional foods, supplements, pills, hard capsules, soft capsules, tablets Sugar-coated tablets, intraoral quick disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, troches, film-coated tablets, etc.].

  The present invention also provides a method for producing a low calorie composition, characterized in that the calorie reducing material of the present invention is used as a raw material of the composition of the present invention.

  In the production method of the present invention, if the calorie reducing material of the present invention is used as a raw material of the composition, the amount used, the addition time, and the addition method are not particularly limited, and other components added and blended are also used without limitation. The amount used and the method of addition can also be appropriately selected according to known techniques. Specifically, for example, carriers, bases, and / or additives that are usually used in the pharmaceutical field, food field, and the like can be appropriately blended within a range that achieves the object of the present invention.

  Moreover, the method of reducing the calorie of the said composition can also be provided as 1 aspect of this invention by mix | blending the raw material for calorie reduction of this invention with a composition. In this case, if the raw material for reducing calories of the present invention is used as a raw material of the composition, the previous item can be referred to.

  In addition, the present invention provides a method for reducing caloric intake, which comprises administering to the individual in need of reducing caloric intake the cyclic dipeptide of the present invention or a salt thereof, or an effective amount of the low calorie composition of the present invention. I will provide a. In this case, the effective amount cannot be generally set, and can be appropriately adjusted according to a desired calorie reduction amount.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

Example 1 Examination of Urinary Excretion Rate after Cyclic Dipeptide Cyclo (Gly-Pro) Administration After purchasing male SD rats (6 weeks old) from Clea Japan, animals acclimated for about 1 week were used for the test. . Cyclo (Gly-Pro) preparation (Bachem) was dissolved in distilled water so as to be 0.3 mg / mL, and was orally administered using a syringe and a sonde so that the dose became 3 mg / kg. The total amount of urine excreted up to 48 hours after the start of administration was collected using a metabolic cage. The collected urine sample was subjected to protein removal treatment after measuring the weight and analyzed under the following conditions using LC-MS / MS (4000QTRAP, ABSCIEX). Quantitative analysis was performed using calibration curve data prepared using a blank urine sample and a standard aqueous solution. Calculate the urinary excretion of Cyclo (Gly-Pro) from the obtained urinary Cyclo (Gly-Pro) concentration and urine weight, and calculate the urinary excretion of Cyclo (Gly-Pro) as Cyclo (Gly-Pro) The urinary excretion rate was calculated by dividing by the dose. The results are shown in Table 2. As a reference example, a linear dipeptide Gly-Pro was also tested in the same manner, and the results are also shown.
<Analysis conditions for LC-MS / MS>
[HPLC conditions]
The following solvents were used for the mobile phase, and the following gradient conditions were applied.
(Basic conditions)
Flow rate: 0.2mL / min Analysis time: 14.0min / sample Column: Cadenza CD-C18 150 (mm) × 2 (mm), particle size 3μm
(Mobile phase)
Phase A: 0.1% formic acid aqueous solution Phase B: 0.1% formic acid-containing acetonitrile (gradient conditions)

[MS / MS conditions]
Measurement mode: MRM potsitive
Q1 / Q3: 155.2> 70.2 (Cyclo (Gly-Pro))
214.1> 155.1 (Internal standard compound: Cyclo (Arg-Gly))
Injection volume: 5μL

  From the above results, it can be seen that almost all of the cyclic dipeptide Cyclo (Gly-Pro) was excreted as unchanged substance without being decomposed. That is, it was clarified that the cyclic dipeptide Cyclo (Gly-Pro) was well absorbed through the intestine and then excreted into the urine via the kidney with almost no degradation by peptidase or the like.

Example 2 Examination of urinary excretion rate after administration of cyclic dipeptide Cyclo (Gly-Tyr) Same as Example 1 except that Cyclo (Gly-Tyr) is used as the cyclic dipeptide and urine recovery time is set to 72 hours The test was conducted. The sample used was a Cyclo (Gly-Tyr) standard (Kobe Natural Products Chemicals).

  The analysis was performed using LC-MS / MS (API5000, ABSCIEX), and the analysis target substances were Cyclo (Gly-Tyr) and Cyclo (Gly-Tyr) -GlcA. (Glucuron conjugate, according to a known synthesis method). The conditions for HPLC and MS analysis were as described below.

Quantitative analysis was performed using calibration curve data prepared using a blank urine sample and a standard aqueous solution. Calculate the urinary excretion amount from the concentration of urinary Cyclo (Gly-Tyr) unchanged substance and metabolite (glucuronic acid conjugate) and the urine weight, and the urinary excretion amount in terms of substance (mole) Was divided by the dose to calculate the urinary excretion rate. The results are shown in Table 4.
<Analysis conditions for LC-MS / MS>
[HPLC conditions]
The following solvents were used for the mobile phase, and the following gradient conditions were applied.
(Basic conditions)
Flow rate: 0.2mL / min Analysis time: 40min / sample Column: Cadenza CD-C18 150 (mm) × 2 (mm), particle size 3μm
(Mobile phase)
Phase A: 0.1% formic acid aqueous solution Phase B: methanol (gradient conditions)

[MS / MS conditions]
Measurement mode: MRM negative
Q1 / Q3: 219> 113 (Unchanged: Cyclo (Gly-Tyr))
395> 113 (Glucuronic acid conjugate: Cyclo (Gly-Tyr) -GlcA.)

  From the above results, it was shown that at least about 40% of the administered cyclo (Gly-Tyr) was excreted in urine without being accumulated in the living body within 72 hours. Considering the possibility of producing other metabolites and the possibility of being excreted in the feces, a higher proportion of compounds excreted in vitro is assumed.

  Hereinafter, the specific prescription of the composition which mix | blended the cyclic dipeptide of this invention or its salt is illustrated. These compositions can be prepared according to known methods.

Production Example 1: Powder for dissolution at time of use As shown in Table 5 below, a composition containing the cyclic dipeptide of the present invention or a salt thereof and other excipients such as ceramide raw material, elastin peptide, proteoglycan, vitamin C, dextrin and the like. A powder for dissolution (6.5 g) at the time of use was manufactured by weighing and mixing to be uniform. When the obtained powder was dissolved in water, all of them had good dispersibility and were suitable as beverages to be used when used.

Production Example 2: Tablet As shown in Table 6 below, a composition containing the cyclic dipeptide of the present invention or a salt thereof and a mixture containing other raw materials were granulated and molded by a conventional method to obtain tablets.

Production Example 3: Collagen Peptide-Containing Beverage A beverage having the following composition was obtained using a composition containing the cyclic dipeptide of the present invention or a salt thereof obtained by a known method using collagen peptide as a raw material.

  The composition for reducing calorie of the present invention is mainly absorbed as a conjugate of a water-soluble molecule such as unchanged substance or glucuronic acid without the cyclic dipeptide contained therein being efficiently absorbed in the living body and being decomposed into free amino acids. Since it is excreted as it is, it is useful for, for example, diet, calorie reduction, or prevention and / or improvement of metabolic syndrome.

Claims (15)

  A calorie reducing composition comprising a cyclic dipeptide or a salt thereof.   The calorie reducing composition according to claim 1, wherein the cyclic dipeptide or a salt thereof contains glycine and / or proline as a constituent.   The composition for reducing calories according to claim 1 or 2, wherein the cyclic dipeptide or a salt thereof is obtained by heat-treating a plant component and / or an animal component.   The composition for calorie reduction according to claim 3, wherein the plant component is one or more extracts selected from the group consisting of soybean, malt, barley, wheat, coffee, black bean, sesame, and tea.   The composition for calorie reduction according to claim 3, wherein the animal component is one or more selected from the group consisting of collagen peptide, milk, whey, casein, and placenta extract.   The composition for reducing calories according to claim 1, wherein the cyclic dipeptide contains cycloglycylproline.   The composition for calorie reduction according to claim 6, wherein the composition is a solid composition, and 0.01 wt (w / w)% or more of cycloglycylproline is contained in the dry solid.   The composition for calorie reduction according to claim 6, wherein the composition is a solid composition and contains 0.1% by weight (w / w)% or more of cycloglycylproline in the dry solid.   The composition for calorie reduction according to claim 6, wherein the composition is a liquid composition and contains 1.0 ppm / Brix or more of cycloglycylproline in the liquid.   The composition for calorie reduction according to claim 6, wherein the composition is a liquid composition and contains 10 ppm / Brix or more of cycloglycylproline in the liquid.   Food / beverage products containing the composition for calorie reduction in any one of Claims 1-10.   The manufacturing method of food-drinks characterized by using the composition for calorie reduction in any one of Claims 1-10.   A method for reducing calories of the composition, which comprises blending a cyclic dipeptide or a salt thereof with the composition.   Use of a cyclic dipeptide or a salt thereof for reducing the calorie of a composition.   A method for reducing caloric intake, comprising a step of administering an effective amount of a cyclic dipeptide or a salt thereof to an individual who needs to reduce caloric intake.