HK1230626A1

HK1230626A1 - Cyclic dipeptide-containing composition

Info

Publication number: HK1230626A1
Application number: HK17104207.2A
Authority: HK
Inventors: 铃木寿荣; 富贵泽伸哉; 别府佳纪; 渡边齐志
Original assignee: 三得利控股株式会社
Priority date: 2014-06-20
Filing date: 2015-02-13
Publication date: 2017-12-08

Description

Composition containing cyclic dipeptide

Technical Field

The present invention relates to a cyclic dipeptide-containing composition.

Background

Two amino acid-bonded "dipeptides" have been attracting attention as functional substances. Dipeptides can add new functions and physical properties that monomer amino acids do not have, and are expected to have applications beyond those of amino acids. Among them, diketopiperazines, which are cyclic dipeptides, are known to have various physiological activities, and their needs in the medical and pharmacological fields are expected to expand.

For example, patent document 1 reports that a cyclic dipeptide having a 2, 5-diketopiperazine structure has an antidepressant action, an effect of improving learning consciousness, and the like. In addition, non-patent document 1 describes that cyclic dipeptide Cyclo (His-Pro) exhibits various physiological activities as follows: the effects on the central nervous system such as lowering body temperature and suppressing appetite, the hormone-like effects such as suppressing prolactin secretion and promoting growth hormone secretion, etc., and it has also been reported that the cyclic dipeptide Cyclo (Leu-Gly) shows a memory function improving effect, and the cyclic dipeptide Cyclo (Asp-Pro) shows a lipotropism suppressing effect. Non-patent document 2 reports a cyclic dipeptide having antibacterial and antioxidant effects.

Non-patent document 3 describes that cyclic dipeptide Cyclo (Trp-Pro) has an anticancer activity, cyclic dipeptides Cyclo (His-Pro) and Cyclo (Gly-Pro) have an antibacterial activity, cyclic dipeptide Cyclo (His-Pro) has a neuroprotective activity, cyclic dipeptide Cyclo (Gly-Pro) has a memory function improving activity, and cyclic dipeptides Cyclo (Tyr-Pro) and Cyclo (Phe-Pro) have an activity as a biological herbicide.

Documents of the prior art

Patent document

Japanese patent publication 1 No. 2012-517998 of Japanese Kokai

Non-patent document

Non-patent document 1Peptides, 16(1), 151-

Non-patent document 2Bioscience & industry (Japanese original name: バイオサイエンスとインダストリー), 60(7), 454-

Non-patent document 3Chemical Reviews, 112, 3641-3716(2012)

Disclosure of Invention

However, cyclic dipeptides have many undefined functions.

The present invention addresses the problem of providing a composition containing a cyclic dipeptide that has an excellent uric acid level lowering effect.

The present invention relates to the following [1] to [3 ].

[1] A cyclic dipeptide-containing composition characterized by containing 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof in amounts satisfying the respective ranges of amounts as described in (1) to (8),

(1) the content of the cycllysyl tyrosine or the salt thereof is 1.00 × 10-1.50 × 10⁵ppm

(2) The content of the cyclic isoleucyl tyrosine or the salt thereof is 0.80 × 10-1.30 × 10⁵ppm

(3) The content of the cyclic threonyl tyrosine or the salt thereof is 0.50 × 10-0.90 × 10⁵ppm

(4) The content of the cyclic aspartyl tyrosine or the salt thereof is 0.10 × 10-0.30 × 10⁵ppm

(5) The content of the cyclic aspartyl tyrosine or the salt thereof is 0.50 × 10-0.90 × 10⁵ppm

(6) The content of the cyclic glutaminyl tyrosine or the salt thereof is 0.30 × 10-0.50 × 10⁵ppm

(7) The content of the cyclamenyl tyrosine or the salt thereof is 1.00 × 10-1.60 × 10⁵ppm

(8) The content of the cyclomethionyl tyrosine or the salt thereof is 0.10 × 10-0.20 × 10⁵ppm。

[2] A cyclic dipeptide-containing composition characterized by containing 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof in amounts satisfying the respective ranges of amounts as described in (1) to (8),

(1) the content of cycllysyltyrosine or its salt is 5.0 × 10^-4～9.0×10mg/100mL

(2) The content of cycloisoleucyl tyrosine or its salt is 4.0 × 10^-4～7.0×10mg/100mL

(3) The content of the cyclic threonyl tyrosine or its salt is 3.0 × 10^-4～5.0×10mg/100mL

(4) The content of the cyclic aspartyl tyrosine or the salt thereof is 1.0 × 10^-4～2.0×10mg/100mL

(5) The content of the cyclic aspartyl tyrosine or the salt thereof is 3.0 × 10^-4～5.0×10mg/100mL

(6) The content of the cyclic glutaminyl tyrosine or its salt is 1.0 × 10^-4～3.0×10mg/100mL

(7) The content of cyclarginyl tyrosine or its salt is 6.0 × 10^-4～1.0×10²mg/100mL

(8) The content of cyclomethionyl tyrosine or its salt is 0.7 × 10^-4～2.0×10mg/100mL。

[3] A cyclic dipeptide-containing composition characterized by containing 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof in amounts satisfying the respective ranges of amounts as described in (1) to (8),

(1) content of cycllysyltyrosine or a salt thereof: 0.01 to 15% by weight

(2) Content of cyclic isoleucyl tyrosine or salt thereof: 0.008 to 13% by weight

(3) Content of cyclic threonyl tyrosine or a salt thereof: 0.005 to 9% by weight

(4) Content of cyclic aspartyl tyrosine or a salt thereof: 0.001 to 3% by weight

(5) Content of cyclic aspartyl tyrosine or a salt thereof: 0.005 to 9% by weight

(6) Content of cyclic glutaminyl tyrosine or a salt thereof: 0.003 to 5% by weight

(7) Content of cyclarginyl tyrosine or a salt thereof: 0.01 to 16% by weight

(8) Content of cyclomethionyl tyrosine or a salt thereof: 0.001 to 2% by weight

The cyclic dipeptide-containing composition of the present invention has an excellent effect of having an excellent uric acid level lowering effect.

Drawings

FIG. 1 is a graph showing the xanthine oxidase inhibition (%) of Cyclo (Tyr-Gly), linear dipeptides Tyr-Gly, Gly-Tyr and amino acid Tyr.

FIG. 2 is a graph showing the results of studies on the effect of decreasing the serum uric acid level of a tyrosine-containing cyclic dipeptide in a hyperuricemic mouse.

FIG. 3 is a graph showing the results of studies on the inhibitory activity of Xanthine Oxidase (XO) against tyrosine-containing cyclic dipeptides in hyperuricemic mice. The upper panel shows the XO activity in the liver, and the lower panel shows the XO activity in the serum.

FIG. 4 is a graph showing the results of examining the effect of decreasing the serum uric acid level of a heat-treated soybean peptide product and a mixture of 8 Tyr-containing cyclic dipeptides contained in the heat-treated soybean peptide product for a hyperuricemic mouse.

FIG. 5 is a graph showing the results of studies on the effect of decreasing serum uric acid levels of hyperuricemic mice by the amount of heat-treated soybean peptide.

Detailed Description

The cyclic dipeptide-containing composition of the present invention has the following characteristics: contains a cyclic tryptophanyl tyrosine [ Cyclo (Trp-Tyr) ], cyclic seryl tyrosine [ Cyclo (Ser-Tyr) ], cyclic prolyl tyrosine [ Cyclo (Pro-Tyr) ], cyclic tyrosyl glycine [ Cyclo (Tyr-Gly) ], cyclic tyrosyl tyrosine [ Cyclo (Tyr-Tyr) ], cyclic phenylalanyl tyrosine [ Cyclo (Phe-Tyr) ], cyclic leucyl tyrosine [ Cyclo (Leu-Tyr) ], cyclic lysyl tyrosine [ Cyclo (Lys-Tyr) ], cyclic histidyl tyrosine [ Cyclo (His-Tyr) ], cyclic alanyl tyrosine [ Cyclo (Ala-Tyr) ], cyclic glutamyl tyrosine [ Cyclo (Glu-Tyr) ], cyclic valyl tyrosine [ Cyclo (Val-Tyr) ], cyclic isoleucyl tyrosine [ Cyclo (Ile-Tyr) ], cyclic threo-Cylo (Thr-Tyr) ], cyclic threo (Thr-Tyr) ], and cyclic tyryl tyrosine [ Cyclo (Tyr) ] 1 or 2 or more cyclic dipeptides among cyclic aspartyltyrosine [ Cyclo (Asp-Tyr) ], cyclic aspartyltyrosine [ Cyclo (Asn-Tyr) ], cyclic glutamyltryrosine [ Cyclo (Gln-Tyr) ], cyclic arginyltyrosine [ Cyclo (Arg-Tyr) ], and cyclic methionyltyrosine [ Cyclo (Met-Tyr) ], or salts thereof, wherein the cyclic dipeptides contain tyrosine, and the content of the cyclic dipeptides or salts thereof is specified. Among them, from the viewpoint of solubility in water, 1 or 2 or more cyclic dipeptides or salts thereof selected from the group consisting of cyclolysyltyrosine [ Cyclo (Lys-Tyr) ], cycloisoleucyltyrosine [ Cyclo (Ile-Tyr) ], cyclothreonyltyrosine [ Cyclo (Thr-Tyr) ], cycloaspartyltyrosine [ Cyclo (Asp-Tyr) ], cycloaspartyltyrosine [ Cyclo (Asn-Tyr) ], cycloglutamyltryrosine [ Cyclo (Gln-Tyr) ], cycloarginyltyrosine [ Cyclo (Arg-Tyr) ], and cyclomethionyltyrosine [ Cyclo (Met-Tyr) ], are preferably contained, and the content of the cyclic dipeptide or salt thereof is preferably a specific amount. The tyrosine-containing cyclic dipeptide may be referred to as a cyclic dipeptide of the present invention or a diketopiperazine of the present invention. In the present specification, if the structures of the amino acids in the cyclic dipeptide are the same, the order of description of these is not critical, and for example, Cyclo (Trp-Tyr) and Cyclo (Tyr-Trp) are the same cyclic dipeptide.

The cyclic dipeptide of the present invention may be any cyclic dipeptide as long as at least one of the constituent amino acids is tyrosine, and for example, when the constituent 2 amino acids are represented by amino acid a and amino acid B, the cyclic dipeptide has a structure in which the carboxyl group of amino acid a and the amino group of amino acid B are dehydration-condensed and the amino group of amino acid a and the carboxyl group of amino acid B are dehydration-condensed. As described above, although the detailed reason why the cyclic dipeptide of the present invention contains tyrosine as its constituent element is not clear, for example, from a comparison of table 1 and table 3 described below, if it is considered that the xanthine oxidase inhibitory action is not confirmed in the cyclic dipeptide containing phenylalanine having the same aromatic ring, it is presumed that the xanthine oxidase activity is inhibited by the phenolic hydroxyl group of tyrosine. However, these assumptions do not limit the present invention.

The cyclic dipeptide-containing composition of the present invention contains 1 or 2 or more cyclic dipeptides among the 19 cyclic dipeptides or salts thereof in a specific amount, and from the viewpoint of excellent solubility in water, it is sufficient if at least 1 cyclic dipeptide or salt thereof selected from the group consisting of cyclic lysyl tyrosine, cyclic isoleucyl tyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, cyclic arginyl tyrosine, and cyclic methionyl tyrosine is contained in a specific amount. The cyclic dipeptides having excellent solubility in water are more preferably those having a solubility in water at 25 ℃ of not less than 1mM, but having a solubility in water at 25 ℃ of not less than 5 mM. In the present specification, the cyclic dipeptide or a salt thereof may be simply referred to as a cyclic dipeptide.

In the present specification, the salt of the cyclic dipeptide refers to any pharmacologically acceptable salt (including inorganic salts and organic salts) of the cyclic dipeptide, and examples thereof include sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, hydrochloride salts, sulfate salts, nitrate salts, phosphate salts, and organic acid salts (e.g., acetate salts, citrate salts, maleate salts, malate salts, oxalate salts, lactate salts, succinate salts, fumarate salts, propionate salts, formate salts, benzoate salts, picrate salts, and benzenesulfonate salts) of the cyclic dipeptide.

The cyclic dipeptide of the present invention can be produced according to a method known in the art. For example, the peptide can be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or can be synthesized by subjecting a linear peptide to dehydration/cyclization reaction, or can be produced by the methods described in Japanese patent laid-open Nos. 2003-252896 and J.peptide Sci.10, 737-737 (2004). In the present invention, a treated product obtained by heat-treating a solution containing a soybean peptide can be preferably used.

Specifically, the treated product obtained by heat-treating a solution containing a soybean peptide is prepared, for example, by dissolving a soybean peptide in water at a concentration of 20 to 500mg/mL and heating the solution at 40 to 150 ℃ for 5 minutes to 120 hours. The obtained treated product may be subjected to filtration, centrifugal separation, concentration, ultrafiltration, freeze-drying, powdering, or the like as required.

Salts of cyclic dipeptides can be easily prepared by any method known in the art by those skilled in the art.

The composition of the present invention is characterized by containing the cyclic dipeptide or the salt thereof in a specific amount, and therefore, the composition can inhibit the activity of xanthine oxidase and further inhibit the production of uric acid, and therefore, the composition can be preferably used for a disease requiring a decrease in uric acid level. Therefore, the composition of the present invention includes a composition in which the cyclic dipeptide or the salt thereof is blended in an amount specified in the present invention.

The disease to be administered with the uric acid level-lowering agent of the present invention is not particularly limited as long as it is a disease in which a therapeutic effect is observed by lowering the blood uric acid level. Examples of the disease include hyperuricemia, gout nodules, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary calculi, renal dysfunction, joint dysfunction, and vascular disorder.

The composition of the present invention is extremely useful for ameliorating or preventing the symptoms of a disease requiring a decrease in uric acid level by the xanthine oxidase inhibitory action of the cyclic dipeptide of the present invention or a salt thereof. That is, the composition of the present invention can be provided as a health functional food or health food to which an expression for preventing and/or improving gout/hyperuricemia is provided, for example, and is a very useful composition for a person with an elevated blood uric acid level, a person with an elevated uric acid level, a person with an intention of purines, a person who wants to prevent hyperuricemia, a person with an intention of preventing gout, a person with an intention of gout, and the like.

The composition of the present invention contains the cyclic dipeptide or a salt thereof in a specific amount, but the following 3 types can be cited depending on the use of the composition. The content of the cyclic dipeptide or salt thereof in each formula can be measured by a known method, for example, by LC-MS/MS.

< mode 1 >)

Embodiment 1 is an extract composition containing the cyclic dipeptide or a salt thereof. The extract composition is, for example, a composition prepared by treating a material containing the cyclic dipeptide or a constituent amino acid of the cyclic dipeptide as it is or a composition containing the product diluted or concentrated and purified according to a known method, and can be directly formulated, and can be used as a raw material for a pharmaceutical product, a health product, a food or drink (health food), or the like.

The content of each cyclic dipeptide or salt thereof in embodiment 1 is as follows.

(1) Cyclotryptophanyl tyrosine or salt thereof

The content in the composition is preferably 0.08 × 10ppm or more, more preferably 0.08 × 10ppm²ppm or more, more preferably 0.16 × 10²ppm or more, and preferably 0.12 × 10⁵ppm or less, more preferably 0.12 × 10⁴ppm or less, more preferably 0.06 × 10⁴Below ppm.

(2) Cycleosyltyrosine or salt thereof

The content in the composition is preferably 0.80 × 10ppm or more, more preferably 0.80 × 10ppm²ppm or more, preferably 1.60 × 10²ppm or more, and preferably 1.30 × 10⁵ppm or less, more preferably 1.30 × 10⁴ppm or less, more preferably 0.65 × 10⁴Below ppm.

(3) Cycloprolyl tyrosine or salt thereof

The content in the composition is preferably 0.40 × 10ppm or more, more preferably 0.40 × 10ppm²ppm or more, more preferably 0.80 × 10²ppm or more, and preferably 0.70 × 10⁵ppm or less, more preferably 0.70 × 10⁴ppm or less, more preferably 0.35 × 10⁴Below ppm.

(4) Cyclotyrosyl glycine or salt thereof

The content in the composition is preferably 0.30 × 10ppm or more, more preferably 0.30 × 10ppm²ppm or more, more preferably 0.60 × 10²ppm or more, and preferably 0.60 × 10⁵ppm or less, more preferably 0.60 × 10⁴ppm or less, more preferably 0.30 × 10⁴Below ppm.

(5) Cyclotyrosyl tyrosine or salt thereof

The content in the composition is preferably 0.10 × 10ppm or more, more preferably 0.10 × 10ppm²ppm or more, more preferably 0.20 × 10²ppm or more, and preferably 0.30 × 10⁵ppm or less, more preferably 0.30 × 10⁴ppm or less, more preferably 0.15 × 10⁴Below ppm.

(6) Cyclophenylalanyl tyrosine or salt thereof

The content in the composition is preferably 0.50 × 10ppm or more, more preferably 0.50 × 10ppm²ppm or more, more preferably 1.00 × 10²ppm or more, and preferably 0.90 × 10⁵ppm or less, more preferably 0.90 × 10⁴ppm or less, more preferably 0.45 × 10⁴Below ppm.

(7) Cycloleucyltyrosine or salt thereof

The content in the composition is preferably 0.70 × 10ppm or more, more preferably 0.70 × 10ppm²ppm or more, preferably 1.40 × 10²ppm or more, preferably 1.10 × 10⁵ppm or less, more preferably 1.10 × 10⁴ppm or less, more preferably 0.55 × 10⁴Below ppm.

(8) Cyclolysyltyrosine or salt thereof

The content in the composition is preferably 1.00 × 10ppm or more, more preferably 1.00 × 10ppm²ppm or more, preferably 2.00 × 10²ppm or more, and preferably 1.50 × 10⁵ppm or less, more preferably 1.50 × 10⁴ppm or less, more preferably 0.75 × 10⁴Below ppm.

(9) Cyclhistidyl tyrosine or salts thereof

The content in the composition is preferably 0.20 × 10ppm or more, more preferably 0.20 × 10ppm²ppm or more, more preferably 0.40 × 10²ppm or more, and preferably 0.40 × 10⁵ppm or less, more preferablyIs 0.40 × 10⁴ppm or less, more preferably 0.20 × 10⁴Below ppm.

(10) Cycloalanyl tyrosine or salt thereof

(11) Cycloglutamyl tyrosine or salt thereof

(12) Cyclovalyl tyrosine or its salt

(13) Cyclic isoleucyl tyrosine or salt thereof

(14) Cyclic threonyl tyrosine or its salt

The content in the composition is preferably 0.50 × 10ppm or more, more preferably 0.5 ppm0×10²ppm or more, more preferably 1.00 × 10²ppm or more, and preferably 0.90 × 10⁵ppm or less, more preferably 0.90 × 10⁴ppm or less, more preferably 0.45 × 10⁴Below ppm.

(15) Cycloaspartyl tyrosine or salt thereof

(16) Cycloaspartyltyrosine or salt thereof

(17) Cycloglutaminyl tyrosine or a salt thereof

The content in the composition is preferably 0.30 × 10ppm or more, more preferably 0.30 × 10ppm²ppm or more, more preferably 0.60 × 10²ppm or more, and preferably 0.50 × 10⁵ppm or less, more preferably 0.50 × 10⁴ppm or less, more preferably 0.25 × 10⁴Below ppm.

(18) Cycloarginyl tyrosine or salt thereof

The content in the composition is preferably 1.00 × 10ppm or more, more preferably 1.00 × 10ppm²ppm or more, preferably 2.00 × 10²ppm or more, and preferably 1.60 × 10⁵ppm or less, more preferably 1.60 × 10⁴ppm or less, more preferably 0.80 × 10⁴Below ppm.

(19) Cyclomethionyl tyrosine or salt thereof

The content in the composition is preferably 0.10 × 10ppm or more, more preferably 0.10 × 10ppm²ppm or more, more preferably 0.20 × 10²ppm or more, and preferably 0.20 × 10⁵ppm or less, more preferably 0.20 × 10⁴ppm or less, more preferably 0.10 × 10⁴Below ppm.

Among them, the cyclic dipeptide or salt thereof in the embodiment 1 may be any component as long as the content of at least 1 component is within the above range, but from the viewpoint of xanthine oxidase inhibitory action, it is desirable that the content of the following cyclic dipeptide or salt thereof is within the above range: preferably 1 or 2 or more cyclic dipeptides or salts thereof selected from the group consisting of cycloserinyl tyrosine, cycloserinyl glycine, cycloserinyl tyrosine, and cycloserinyl tyrosine; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosylglycine, cyclotyrosyltyrosine, cyclophenylalanyltyrosine, cycloleucyltyrosine, cyclovalyltyrosine, cycloisoleucyltyrosine, and cyclomethionyltyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, and cycloleucyl tyrosine, or salts thereof; further preferred is cyclotyrosyl tyrosine or a salt thereof.

From the viewpoint of solubility in water, the following cyclic dipeptide or salt thereof is desirably contained in the range described above: preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, cyclic arginyl tyrosine, and cyclic methionyl tyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, and cyclic arginyl tyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, and cyclic arginyltyrosine, or salts thereof. In addition, although any component may be contained as the component to be combined with the above-mentioned components, from the viewpoint of xanthine oxidase inhibitory action, the following cyclic dipeptide or salt thereof is desirably contained in an amount within the above-mentioned range: preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cycloserinyl tyrosine, cyclotyrosyl glycine, cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine, and cyclovalyl tyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosylglycine, cyclotyrosyltyrosine, cyclophenylalanyltyrosine, cycloleucyltyrosine, and cyclovalyltyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from tyrosyl tyrosine, cyclophenylalanyl tyrosine and cycloleucyl tyrosine, or salts thereof; further preferred is cyclotyrosyl tyrosine or a salt thereof.

The number of components satisfying the content of each component listed above is preferably 1 component or more, more preferably 3 components or more, further preferably 4 components or more, further preferably 6 components or more, further preferably 7 components or more, further preferably 8 components or more, and further preferably 11 components or more. Specifically, for example, from the viewpoint of xanthine oxidase inhibitory action, the content of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine and cycloleucyl tyrosine is preferably within the above range; more preferably, the content of cyclotyrosylglycine, cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine, cyclovalyl tyrosine, cycloisoleucyl tyrosine and cyclomethionyl tyrosine is within the aforementioned range; further preferably, the content of cycloserinyl tyrosine, cycloserinyl glycine, cycloserinyl tyrosine and cycloserinyl tyrosine is in the aforementioned range. From the viewpoint of solubility in water, the content of cyclic lysyl tyrosine, cyclic isoleucyl tyrosine, cyclic threonyl tyrosine, and cyclic arginyl tyrosine is preferably within the above range; more preferably, the content of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine and cyclic arginyl tyrosine is within the aforementioned range; it is further preferable that the content of cyclic lysyl tyrosine, cyclic isoleucyl tyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, cyclic arginyl tyrosine and cyclic methionyl tyrosine is within the aforementioned range.

The content of the cyclic dipeptide or salt thereof in embodiment 1 is as described above for each component, but the total content of the cyclic dipeptide or salt thereof is preferably 8.0 × 10ppm or more, and more preferably 8.0 × 10ppm²ppm or more, preferably 1.6 × 10³ppm or more, and preferably 1.0 × 10⁶ppm or less, more preferably 1.4 × 10⁵ppm or less, more preferably 0.7 × 10⁵Below ppm.

The total content of cyclotyrosyltyrosine, cyclophenylalanyl tyrosine, cycloleucyltyrosine and salts thereof having a strong xanthine oxidase inhibitory activity in embodiment 1 is preferably 1.3 × 10ppm or more, more preferably 1.3 × 10ppm²ppm or more, preferably 2.6 × 10²ppm or more, and preferably 2.3 × 10⁵ppm or less, more preferably 2.3 × 10⁴ppm or less, more preferably 1.15 × 10⁴Below ppm.

From the viewpoint of xanthine oxidase inhibitory effect, the ratio of the sum of cyclotyrosyltyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine, and salts thereof having a strong xanthine oxidase inhibitory effect in the cyclic dipeptide in the embodiment 1 is preferably 5% by weight or more, more preferably 10% by weight or more, and further preferably 15% by weight or more. Although the upper limit is not particularly limited, from the viewpoint of the solubilizing performance, it is preferably 90% by weight or less, and more preferably 60% by weight or less.

In addition, the weight ratio [ Cyclo (Tyr-Phe)/Cyclo (Tyr-Tyr) ] of the cyclophenylalanyl tyrosine to the cyclotyrosyl tyrosine is preferably 95/5 to 35/65, more preferably 90/10 to 40/60, and still more preferably 90/10 to 50/50, from the viewpoint of the xanthine oxidase inhibitory effect.

In addition, the weight ratio [ Cyclo (Phe-Tyr)/Cyclo (Tyr-Gly) ] of the cyclophenylalanyl tyrosine to the cyclotyrosyl glycine is preferably 90/10 to 30/70, more preferably 90/10 to 40/60, and still more preferably 90/10 to 50/50, from the viewpoint of the xanthine oxidase inhibitory effect.

The total content of cyclolysyltyrosine, cycloarginyltyrosine, and salts thereof having high solubility in water in embodiment 1 is preferably 2.00 × 10ppm or more, and more preferably 2.00 × 10ppm²ppm or more, more preferably 4.00 × 10²ppm or more, and preferably 3.10 × 10⁵ppm or less, more preferably 3.10 × 10⁴ppm or less, more preferably 1.55 × 10⁴Below ppm.

In the cyclic dipeptide according to embodiment 1, the ratio of the total amount of the cyclic lysyltyrosine, the cyclic arginyltyrosine, and the salt thereof having high solubility in water is preferably 5% by weight or more, more preferably 10% by weight or more, and still more preferably 15% by weight or more, from the viewpoint of preparing a composition. Although the upper limit is not particularly limited, it is preferably 90% by weight or less, and more preferably 60% by weight or less, from the viewpoint of the solubilizing performance.

The composition of the embodiment 1 can be prepared, for example, by adding a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient, a binder, a disintegrant, a lubricant, etc., to a raw material containing the cyclic dipeptide or the salt thereof, and can be prepared into solid preparations such as tablets, granules, powders, capsules, etc., or liquid preparations such as general liquids, suspensions, emulsions, etc., according to a known method. These compositions can be taken directly with water or the like. In addition, the compound can be prepared in a form that can be easily incorporated (for example, a powder form or a granule form), and then used as a raw material for, for example, a pharmaceutical product, a health product, a food or drink (health food), or the like.

Specific examples of the composition of embodiment 1 include solid agents such as tablets, granules, powders and capsules, and liquid agents such as liquid agents, suspensions and emulsions.

< mode 2 >

Embodiment 2 is a beverage composition containing the cyclic dipeptide or a salt thereof. The beverage composition is a composition mainly used for drinking, and the content of each cyclic dipeptide or salt thereof in embodiment 2 is as follows.

(1) Cyclotryptophanyl tyrosine or salt thereof

The content in the composition is preferably 0.4 × 10^-4mg/100mL or more, more preferably 0.4 × 10^-3mg/100mL or more, more preferably 0.8 × 10^-3mg/100mL or more, and preferably 0.7 × 10mg/100mL or less, more preferably 0.7mg/100mL or less, and still more preferably 3.5 × 10^-1mg/100mL or less.

(2) Cycleosyltyrosine or salt thereof

The content in the composition is preferably 4.0 × 10^-4mg/100mL or more, more preferably 4.0 × 10^-3mg/100mL or more, more preferably 8.0 × 10^-3mg/100mL or more, and preferably 8.0 × 10mg/100mL or less, more preferably 8.0mg/100mL or less, and further preferably 4.0mg/100mL or less.

(3) Cycloprolyl tyrosine or salt thereof

The content in the composition is preferably 2.0 × 10^-4mg/100mL or more, more preferably 2.0 × 10^-3mg/100mL or more, more preferably 4.0 × 10^-3mg/100mL or more, and preferably 4.0 × 10mg/100mL or less, more preferably 4.0mg/100mL or less, and further preferably 2.0mg/100mL or less.

(4) Cyclotyrosyl glycine or salt thereof

(5) Cyclotyrosyl tyrosine or salt thereof

The content in the composition is preferably 0.8 × 10^-4mg/100mL or more, more preferably 0.8 × 10^-3mg/100mL or more, more preferably 1.6 × 10^-3mg/100mL or more, and preferably 2.0 × 10mg/100mL or less, more preferably 2.0mg/100mL or less, and further preferably 1.0mg/100mL or less.

(6) Cyclophenylalanyl tyrosine or salt thereof

The content in the composition is preferably 3.0 × 10^-4mg/100mL or more, more preferably 3.0 × 10^-3mg/100mL or more, more preferably 6.0 × 10^-3mg/100mL or more, and preferably 5.0 × 10mg/100mL or less, more preferably 5.0mg/100mL or less, and further preferably 2.5mg/100mL or less.

(7) Cycloleucyltyrosine or salt thereof

The content in the composition is preferably 4.0 × 10^-4mg/100mL or more, more preferably 4.0 × 10^-3mg/100mL or more, more preferably 8.0 × 10^-3mg/100mL or more, and preferably 7.0 × 10mg/100mL or less, more preferably 7.0mg/100mL or less, and further preferably 3.5mg/100mL or less.

(8) Cyclolysyltyrosine or salt thereof

The content in the composition is preferably 5.0 × 10^-4mg/100mL or more, more preferably 5.0 × 10^-3mg/100mL or more, more preferably 1.0 × 10^-2mg/100mL or more, and preferably 9.0 × 10mg/100mL or less, more preferablyIs 9.0mg/100mL or less, and more preferably 4.5mg/100mL or less.

(9) Cyclhistidyl tyrosine or salts thereof

The content in the composition is preferably 1.0 × 10^-4mg/100mL or more, more preferably 1.0 × 10^-3mg/100mL or more, more preferably 2.0 × 10^-3mg/100mL or more, and preferably 3.0 × 10mg/100mL or less, more preferably 3.0mg/100mL or less, and further preferably 1.5mg/100mL or less.

(10) Cycloalanyl tyrosine or salt thereof

(11) Cycloglutamyl tyrosine or salt thereof

The content in the composition is preferably 1.0 × 10^-4mg/100mL or more, more preferably 1.0 × 10^-3mg/100mL or more, more preferably 2.0 × 10^-3mg/100mL or more, and preferably 2.0 × 10mg/100mL or less, more preferably 2.0mg/100mL or less, and further preferably 1.0mg/100mL or less.

(12) Cyclovalyl tyrosine or its salt

(13) Cyclic isoleucyl tyrosine or salt thereof

The content in the composition is preferably 4.0 × 10^-4mg/100mL or more, more preferably 4.0 × 10^-3mg/100mL toAbove, more preferably 8.0 × 10^-3mg/100mL or more, and preferably 7.0 × 10mg/100mL or less, more preferably 7.0mg/100mL or less, and further preferably 3.5mg/100mL or less.

(14) Cyclic threonyl tyrosine or its salt

(15) Cycloaspartyl tyrosine or salt thereof

(16) Cycloaspartyltyrosine or salt thereof

(17) Cycloglutaminyl tyrosine or a salt thereof

(18) Cycloarginyl tyrosine or salt thereof

The content in the composition is preferably 6.0 × 10^-4mg/100mL or more, more preferably 6.0 × 10^-3mg/100mL or more, more preferably 1.2 × 10^-2mg/100mL or more, and preferably 1.0 × 10²mg/100mL or less, more preferably 1.0 × 10mg/100mL or less, and still more preferably 5.0mg/100mL or less.

(19) Cyclomethionyl tyrosine or salt thereof

The content in the composition is preferably 0.7 × 10^-4mg/100mL or more, more preferably 0.7 × 10^-3mg/100mL or more, more preferably 1.4 × 10^-3mg/100mL or more, and preferably 2.0 × 10mg/100mL or less, more preferably 2.0mg/100mL or less, and further preferably 1.0mg/100mL or less.

Among them, the cyclic dipeptide or salt thereof in the embodiment 2 may be any component as long as the content of at least 1 component is within the above range, but from the viewpoint of xanthine oxidase inhibitory action, it is desirable that the content of the following cyclic dipeptide or salt thereof is within the above range: preferably 1 or 2 or more cyclic dipeptides or salts thereof selected from the group consisting of cycloserinyl tyrosine, cycloserinyl glycine, cycloserinyl tyrosine, and cycloserinyl tyrosine; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosylglycine, cyclotyrosyltyrosine, cyclophenylalanyltyrosine, cycloleucyltyrosine, cyclovalyltyrosine, cycloisoleucyltyrosine, and cyclomethionyltyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, and cycloleucyl tyrosine, or salts thereof; further preferred is cyclotyrosyl tyrosine or a salt thereof.

From the viewpoint of solubility in water, the following cyclic dipeptide or salt thereof is desirably contained in the range described above: preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, cyclic arginyl tyrosine, and cyclic methionyl tyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, and cyclic arginyl tyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, and cyclic arginyl tyrosine, or salts thereof. In addition, as the component to be combined with the above-mentioned components, although any component may be contained, from the viewpoint of xanthine oxidase inhibitory action, the following cyclic dipeptide or salt thereof is desirably contained in the range described above: preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cycloserinyl tyrosine, cyclotyrosyl glycine, cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine, and cyclovalyl tyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosylglycine, cyclotyrosyltyrosine, cyclophenylalanyltyrosine, cycloleucyltyrosine, and cyclovalyltyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, and cycloleucyl tyrosine, or salts thereof; further preferred is cyclotyrosyl tyrosine or a salt thereof.

The content of the cyclic dipeptide or salt thereof in embodiment 2 is as described above for each component, but the total content of the cyclic dipeptide or salt thereof is preferably 5.0 × 10^-3mg/100mL or more, more preferably 5.0 × 10^-2mg/100mL or more, more preferably 1.0 × 10^-1mg/100mL or more, and preferably 8.0 × 10²mg/100mL or less, more preferably 8.0 × 10mg/100mL or less, and still more preferably 4.0 × 10mg/100mL or less.

The total content of cyclotyrosyltyrosine, cyclophenylalanyltyrosine, cycloleucyltyrosine and salts thereof having a strong xanthine oxidase inhibitory action in embodiment 2 is preferably 7.8 × 10^-4mg/100mL or more, more preferably 7.8 × 10^-3mg/100mL or more, more preferably 1.56 × 10^-2mg/100mL or more, and preferably 1.4 × 10mg/100mL or less, more preferably 1.4mg/100mL or less, and further preferably 0.7mg/100mL or less.

From the viewpoint of xanthine oxidase inhibitory effect, the ratio of the sum of cyclotyrosyltyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine and salts thereof having a strong xanthine oxidase inhibitory effect in the cyclic dipeptide in the embodiment 2 is preferably 5% by weight or more, more preferably 10% by weight or more, and further preferably 15% by weight or more. Although the upper limit is not particularly limited, from the viewpoint of the solubilizing performance, it is preferably 90% by weight or less, and more preferably 60% by weight or less.

The total content of cyclolysyltyrosine, cycloarginyltyrosine, and salts thereof having high solubility in water in embodiment 2 is preferably 11.0 × 10^-4mg/100mL or more, more preferably 11.0 × 10^-3mg/100mL or more, more preferably 2.2 × 10^-2mg/100mL or more, and preferably 19.0 × 10mg/100mL or less, more preferably 19.0mg/100mL or less, and further preferably 9.5mg/100mL or less.

From the viewpoint of preparing a composition, the ratio of the total amount of the cyclic dipeptide in embodiment 2, which is the cyclic lysyltyrosine, the cyclic arginyltyrosine, and the salt thereof, which have high solubility in water, is preferably 5% by weight or more, more preferably 10% by weight or more, and still more preferably 15% by weight or more. Although the upper limit is not particularly limited, from the viewpoint of the solubilizing performance, it is preferably 90% by weight or less, and more preferably 60% by weight or less.

The composition of the embodiment 2 can be prepared, for example, by mixing the cyclic dipeptide or the salt thereof in a predetermined amount with the raw materials in the preparation of a known beverage composition and preparing the mixture according to a known method for preparing a beverage composition, or by adding the cyclic dipeptide or the salt thereof to the prepared known beverage composition so as to be in the predetermined amount and dissolving and/or suspending the mixture. The known beverage composition may be a composition originally containing the cyclic dipeptide or a salt thereof, and the cyclic dipeptide of the present invention may be appropriately blended to prepare the beverage composition as long as the amount thereof is a predetermined amount.

Specific examples of the composition of embodiment 2 include nonalcoholic beverages such as oolong tea beverage, black tea beverage, green tea beverage, fruit juice beverage, vegetable juice, sports beverage, isotonic beverage, enhanced water beverage (enhanced water), mineral water, near water beverage (Nearwater), coffee beverage, nutritional health beverage, beauty health beverage, and nonalcoholic and beer-taste beverage; beer, wine, sake, plum wine, sparkling wine, whisky, brandy, distilled liquor, rum, gin, liqueur, etc. In addition, the following may be blended alone or in combination in the composition of the embodiment 2: additives such as antioxidant, perfume, organic acid salt, inorganic acid salt, inorganic salt, pigment, emulsifier, antiseptic, flavoring agent, sweetener, sour material, rubber, oil, vitamin, amino acid, fruit juice extract, vegetable extract, pH regulator, and quality stabilizer.

< mode 3 >

Embodiment 3 is a food composition comprising the cyclic dipeptide or a salt thereof. The food composition is a composition mainly intended to be ingested via diet or snack, and the content of each cyclic dipeptide or salt thereof in embodiment 3 is as follows.

(1) Cyclotryptophanyl tyrosine or salt thereof

The content in the composition is preferably 0.0008 wt% or more, more preferably 0.008 wt% or more, further preferably 0.016 wt% or more, and preferably 1.2 wt% or less, more preferably 0.12 wt% or less, further preferably 0.06 wt% or less.

(2) Cycleosyltyrosine or salt thereof

The content in the composition is preferably 0.008 wt% or more, more preferably 0.08 wt% or more, further preferably 0.16 wt% or more, and preferably 13 wt% or less, more preferably 1.3 wt% or less, further preferably 0.65 wt% or less.

(3) Cycloprolyl tyrosine or salt thereof

The content in the composition is preferably 0.004 wt% or more, more preferably 0.04 wt% or more, further preferably 0.08 wt% or more, and preferably 7 wt% or less, more preferably 0.7 wt% or less, further preferably 0.35 wt% or less.

(4) Cyclotyrosyl glycine or salt thereof

The content in the composition is preferably 0.003% by weight or more, more preferably 0.03% by weight or more, further preferably 0.06% by weight or more, and preferably 6% by weight or less, more preferably 0.6% by weight or less, further preferably 0.3% by weight or less.

(5) Cyclotyrosyl tyrosine or salt thereof

The content in the composition is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, further preferably 0.02% by weight or more, and preferably 3% by weight or less, more preferably 0.3% by weight or less, further preferably 0.15% by weight or less.

(6) Cyclophenylalanyl tyrosine or salt thereof

The content in the composition is preferably 0.005% by weight or more, more preferably 0.05% by weight or more, further preferably 0.10% by weight or more, and preferably 9% by weight or less, more preferably 0.9% by weight or less, further preferably 0.45% by weight or less.

(7) Cycloleucyltyrosine or salt thereof

The content in the composition is preferably 0.007% by weight or more, more preferably 0.07% by weight or more, further preferably 0.14% by weight or more, and preferably 11% by weight or less, more preferably 1.1% by weight or less, further preferably 0.55% by weight or less.

(8) Cyclolysyltyrosine or salt thereof

The content in the composition is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, further preferably 0.2% by weight or more, and preferably 15% by weight or less, more preferably 1.5% by weight or less, further preferably 0.75% by weight or less.

(9) Cyclhistidyl tyrosine or salts thereof

The content in the composition is preferably 0.002% by weight or more, more preferably 0.02% by weight or more, further preferably 0.04% by weight or more, and preferably 4% by weight or less, more preferably 0.4% by weight or less, further preferably 0.2% by weight or less.

(10) Cycloalanyl tyrosine or salt thereof

(11) Cycloglutamyl tyrosine or salt thereof

(12) Cyclovalyl tyrosine or its salt

(13) Cyclic isoleucyl tyrosine or salt thereof

(14) Cyclic threonyl tyrosine or its salt

(15) Cycloaspartyl tyrosine or salt thereof

(16) Cycloaspartyltyrosine or salt thereof

(17) Cycloglutaminyl tyrosine or a salt thereof

The content in the composition is preferably 0.003% by weight or more, more preferably 0.03% by weight or more, further preferably 0.06% by weight or more, and preferably 5% by weight or less, more preferably 0.5% by weight or less, further preferably 0.25% by weight or less.

(18) Cycloarginyl tyrosine or salt thereof

The content in the composition is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, further preferably 0.2% by weight or more, and preferably 16% by weight or less, more preferably 1.6% by weight or less, further preferably 0.8% by weight or less.

(19) Cyclomethionyl tyrosine or salt thereof

The content in the composition is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, further preferably 0.02% by weight or more, and preferably 2% by weight or less, more preferably 0.2% by weight or less, further preferably 0.1% by weight or less.

The cyclic dipeptide or salt thereof in embodiment 3 may be any component as long as the content of at least 1 component is within the above range, but from the viewpoint of xanthine oxidase inhibitory action, the content of the following cyclic dipeptide or salt thereof is desirably within the above range: preferably 1 or 2 or more cyclic dipeptides or salts thereof selected from the group consisting of cycloserinyl tyrosine, cycloserinyl glycine, cycloserinyl tyrosine, and cycloserinyl tyrosine; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosylglycine, cyclotyrosyltyrosine, cyclophenylalanyltyrosine, cycloleucyltyrosine, cyclovalyltyrosine, cycloisoleucyltyrosine, and cyclomethionyltyrosine, or salts thereof; more preferably 1 or 2 or more cyclic dipeptides selected from the group consisting of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, and cycloleucyl tyrosine, or salts thereof; further preferred is cyclotyrosyl tyrosine or a salt thereof.

The number of components satisfying the content of each component listed above is preferably 1 component or more, more preferably 3 components or more, further preferably 4 components or more, further preferably 6 components or more, further preferably 7 components or more, further preferably 8 components or more, and further preferably 11 components or more. Specifically, for example, from the viewpoint of xanthine oxidase inhibitory action, the content of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine and cycloleucyl tyrosine is preferably within the above range; more preferably, the content of cyclotyrosylglycine, cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine, cyclovalyl tyrosine, cycloisoleucyl tyrosine and cyclomethionyl tyrosine is within the aforementioned range; further preferably, the content of cycloserinyl tyrosine, cycloserinyl glycine, cycloserinyl tyrosine and cycloserinyl tyrosine is in the aforementioned range. From the viewpoint of solubility in water, the content of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, and cyclic arginyltyrosine is preferably within the above range, and the content of cyclic lysyltyrosine, cyclic isoleucyltyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutaminyl tyrosine, and cyclic arginyltyrosine is more preferably within the above range; it is further preferable that the content of cyclic lysyl tyrosine, cyclic isoleucyl tyrosine, cyclic threonyl tyrosine, cyclic aspartyl tyrosine, cyclic glutamyl tyrosine, cyclic arginyl tyrosine and cyclic methionyl tyrosine is within the aforementioned range.

Although the content of the cyclic dipeptide or salt thereof in the embodiment 3 is as described above for each component, the total content of the cyclic dipeptide or salt thereof is preferably 0.008 wt% or more, more preferably 0.08 wt% or more, further preferably 0.16 wt% or more, and preferably 100 wt% or less, more preferably 80 wt% or less, further preferably 60 wt% or less.

The total content of cyclotyrosyl tyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine, and salts thereof having a strong xanthine oxidase inhibitory action in embodiment 3 is preferably 0.013% by weight or more, more preferably 0.13% by weight or more, further preferably 0.26% by weight or more, and preferably 23% by weight or less, more preferably 17.3% by weight or less, further preferably 11.5% by weight or less.

From the viewpoint of xanthine oxidase inhibitory effect, the ratio of the total amount of cyclotyrosyltyrosine, cyclophenylalanyl tyrosine, cycloleucyl tyrosine and salts thereof having a strong xanthine oxidase inhibitory effect in the cyclic dipeptide in the embodiment 3 is preferably 5% by weight or more, more preferably 10% by weight or more, and further preferably 15% by weight or more. Although the upper limit is not particularly limited, from the viewpoint of the solubilizing performance, it is preferably 90% by weight or less, and more preferably 60% by weight or less.

Further, from the viewpoint of the xanthine oxidase inhibitory effect, the weight ratio [ Cyclo (Phe-Tyr)/Cyclo (Tyr-Gly) ] of the cyclophenylalanyl tyrosine to the cyclotyrosyl glycine is preferably 90/10 to 30/70, more preferably 90/10 to 40/60, and still more preferably 90/10 to 50/50.

The total content of the cyclic lysyltyrosine, the cyclic arginyltyrosine, and the salt thereof having high solubility in water in embodiment 3 is preferably 0.02% by weight or more, more preferably 0.2% by weight or more, further preferably 0.4% by weight or more, and preferably 31% by weight or less, more preferably 3.1% by weight or less, further preferably 1.55% by weight or less.

From the viewpoint of preparing a composition, the proportion of the cyclic dipeptide in embodiment 3 in the total amount of the cyclic lysyltyrosine, the cyclic arginyltyrosine, and the salt thereof, which are highly soluble in water, is preferably at least wt%, more preferably at least wt%, and still more preferably at least wt%. Although the upper limit is not particularly limited, from the viewpoint of the solubilizing performance, it is preferably not more than wt%, and more preferably not more than wt%.

The composition of the embodiment 3 can be prepared, for example, by mixing the cyclic dipeptide or the salt thereof in a predetermined amount with the raw material in the preparation of a known food composition and preparing the mixture according to a known method for producing a food composition, or by adding the cyclic dipeptide or the salt thereof to the prepared known food composition so as to be in the predetermined amount. The known food composition may be a composition originally containing the cyclic dipeptide or a salt thereof, and the cyclic dipeptide of the present invention may be appropriately blended to prepare the food composition as long as the amount thereof is a predetermined amount.

Specific examples of the composition of embodiment 3 include soft canned foods, seasonings (e.g., sauce, soup, salad dressing, mayonnaise, and cream), confectionery (e.g., baked confectionery such as bread, cake, cookie, and biscuit, chewing gum, chocolate, and candy), and desserts (e.g., jelly, yogurt, and ice cream). The form of the food or drink is not particularly limited, and may be any form such as solid, powder, liquid, gel, and slurry, as long as it is easily ingestible. Can also be used in combination with the following cuisine: cooking with purine-rich food materials such as liver, fish white, shrimp, sardine, and skipjack (fish, shrimp, and shellfish); dumpling, potato stewed meat, braised pork, hamburger, etc. are suitable for beer taste beverage.

The composition of the present invention can be ingested by an appropriate method depending on the form thereof. The method of taking the cyclic dipeptide or salt thereof of the present invention is not particularly limited as long as it allows the cyclic dipeptide or salt thereof to move in the circulating blood. In addition, in the present specification, ingestion includes all modes of ingestion, taking or drinking.

The amount of the composition of the present invention to be ingested is appropriately set depending on the form, administration method, purpose of use, and age, weight, and symptoms of the subject to be ingested, i.e., the patient or animal. For example, the effective human body intake amount of the cyclic dipeptide or salt thereof of the present invention is preferably 0.2mg or more, more preferably 2mg or more, and further preferably 20mg or more per day in a human body having a body weight of 50 kg; and is preferably 10g or less, more preferably 5g or less, and further preferably 2g or less. Further, within the desired dose range, the administration may be performed in a single dose or in multiple doses over 1 day. The administration period is also arbitrary. The effective amount of the cyclic dipeptide or salt thereof taken into the human body in the present invention is the total amount of the cyclic dipeptide or salt thereof taken into the human body, which shows an effective effect in the human body, and the kind of the cyclic dipeptide is not particularly limited.

In the present specification, although a human who requires a decrease in blood uric acid level is preferably the subject to be ingested with the composition of the present invention, the subject may be a livestock animal such as a cow, a horse, or a goat, a pet animal such as a dog, a cat, or a rabbit, or an experimental animal such as a mouse, a rat, a guinea pig, or a monkey.

Examples

The present invention will be specifically described with reference to the following examples, but the present invention is not limited to the following examples.

< reagent >

As the cyclic dipeptide, a cyclic dipeptide synthesized by Nippon Kogyo Chemicals was used. The following reagents or preparations were used, respectively: xanthine, sodium carboxymethyl cellulose (CMC-Na), tyrosine (Tyr), formic acid (a special reagent for column chromatography), and methanol (for high performance liquid chromatography) manufactured by Nacalai Tesque, Japan; allopurinol and potassium oxonate (Potasumoxonate) salt are manufactured by Japan and Wako pure chemical industries, Ltd.; xanthine oxidase was manufactured by eastern Japan; the xanthine oxidase detection kit is manufactured by Cayman Chemical Company of the United states; L-Tyrosylglycine is manufactured by Santa Cruz Biotechnology, USA; Glycyl-L-tyrosine, manufactured by Sigma-Aldrich, USA; a tissue protein extraction reagent (T-PER), a protease inhibitor mixture kit, a Pierce BCA protein quantification kit and a polystyrene black 96-well plate are manufactured by Thermo Scientific corporation of America; the heparin sodium salt is manufactured by Holtian pharmaceutical company of Japan; pravastatin (pravastatin) sodium salt manufactured by SIGMA corporation of America; soybean peptide [ HINUTE AM (trade name) ] is manufactured by NOISHI OIL CRYSTAL CORPORATION.

< statistical analysis >

In the following test examples, data are expressed as mean ± standard error. Statistical tests were performed using Student's t-test in test example 1 and Dunnet' test after one-way ANOVA in the other test examples. In the results, "#" indicates a significant difference of p <0.05 and "# indicates a significant difference of p < 0.1. All of these analyses were carried out by SPSS for Windows (registered trademark) release 17.0 (manufactured by SPSS Co.).

Test example 1 (study of XO inhibitory Effect in vitro)

In vitro Xanthine Oxidase (XO) inhibition studies were performed on 210 cyclic dipeptides, linear dipeptides Tyr-Gly, Gly-Tyr and amino acid Tyr.

Specifically, 75. mu.L of 4U/L Xanthine Oxidase (XO) dissolved in Phosphate Buffer Solution (PBS) at pH7.5 was added to each well of a 96-well plate, and 5. mu.L of the sample solution was added thereto so that the final concentration of peptide or amino acid to XO became a predetermined concentration, followed by mixing for 5 minutes (the final concentration of peptide or amino acid was 50 to 500. mu.M). Then, 20. mu.L of a 250. mu.M xanthine solution dissolved in PBS was added thereto, and the absorbance after 30 minutes was measured by a spectrophotometer (Synegy HT, manufactured by Bio Tek, USA). XO inhibitory rate (%) at each concentration was calculated by the following calculation formula, and XO inhibitory activity (IC) was obtained₅₀Value). Table 1 shows xanthine oxidase inhibitory activities (IC) of 12 Tyr-containing cyclic dipeptides₅₀Values), the xanthine oxidase inhibition ratios (%) at 100. mu.M of the 8 Tyr-containing cyclic dipeptides are shown in Table 2, and the xanthine oxidase inhibition activities (IC) of the 20 Phe-containing cyclic dipeptides are shown in Table 3₅₀Value). In addition, allopurinol (IC), a known uric acid level lowering agent, was used₅₀The value: 12.5 μ M) as a positive control.

[ number 1]

A: absorbance at 295nm for enzyme-added and sample non-added groups

B: absorbance at 295nm for enzyme non-added and sample non-added groups

C: absorbance at 295nm for enzyme added and sample added groups

D: absorbance at 295nm for the enzyme non-added and sample added groups

[ Table 1]

[ Table 2]

[ Table 3]

As is clear from tables 1 and 2, the Tyr-containing cyclic dipeptide has XO inhibitory activity; as can be seen from table 3, when Tyr is replaced with Phe, XO inhibitory activity is decreased.

XO inhibition (%) was also measured for Cyclo (Tyr-Gly), linear dipeptides Tyr-Gly, Gly-Tyr, and amino acid Tyr. The results are shown in FIG. 1.

As is clear from fig. 1, the XO inhibitory activity is exhibited by cyclization, suggesting that cyclic dipeptides are important.

Test example 2 (study on the effect of reducing serum uric acid level in hyperuricemia mice)

The effect of lowering the serum uric acid level derived from the cyclic dipeptide in hyperuricemia model animals was investigated.

Animals were male 7-week-old BALBC mice purchased from the company CLEA, Japan, and subjected to an experiment after an acclimation period of 1 week. Animals are raised in a raising room with air conditioning equipment (temperature 23.5 +/-1.0 ℃, humidity 55 +/-10 RH%, ventilation frequency 12-15 times/hour, illumination 7: 00-19: 00/day). During the acclimatization period, a commercial feed (CE-2, manufactured by CLEA, Japan) and distilled water were freely taken.

Oxazinic acid is a substance that increases the blood uric acid level by inhibiting uricase, which is a metabolic enzyme of uric acid. Therefore, hyperuricemia model animals were prepared by administering Potassium Oxonate (PO) (see Planta Med 2009; 75: 302-. The following 6 groups were used for the study. 1) Normal group (Normal group, no oxazinic acid load); 2) PO dosing group (PO group, ofloxacin load); 3) PO + allopurinol 1mg/kg administration group (PO + AL group); 4) PO + Cyclo (Tyr-Gly)10mg/kg administration group (PO + CTG 10 group); 5) PO + Cyclo (Tyr-Gly)30mg/kg administration group (PO + CTG 30 group); 6) PO + Cyclo (Tyr-Gly)100mg/kg administration group (PO + CTG 100 group) (each group n is 6-8). 250mg/kg PO suspended in 0.5% CMC-Na aqueous solution in all groups with PO administration and 0.5% CMC-Na aqueous solution in Normal group were administered intraperitoneally, respectively. After the next 1 hour, 1mg/kg of allopurinol in the PO + allopurinol administration group, 10, 30, and 100mg/kg of Cyclo (Tyr-Gly) in the PO + Cyclo (Tyr-Gly) administration group, and distilled water in the Normal group were orally administered, respectively. Blood was collected from the abdominal vena cava under anesthesia 2 hours after PO administration, and the liver was harvested after exsanguination. The collected blood was left to stand at room temperature for 45 minutes, and then centrifuged at 8000rpm for 10 minutes, and the serum was recovered. In addition, serum and liver were stored at-80 ℃ before the assay.

The uric acid level in serum was measured by a 7180 clinical analyzer (manufactured by Hitachi Technologies, Japan). The results are shown in FIG. 2.

Next, the liver of the mouse was homogenized by adding the mixture of the ice-cooled protease inhibitor mixture and the EDTA-containing cathepsin extraction reagent (T-PER), and then centrifuged at 15000rpm and 4 ℃ for 15 minutes, and the collected supernatant was subjected to measurement of Xanthine Oxidase (XO) activity. XO activity in liver and serum was measured using a xanthine oxidase assay kit and a polystyrene black 96-well plate. Specifically, 50. mu.L of XO standard sample, liver sample or serum sample was added, and then 50. mu.L of the assay mixture prepared by mixing detection buffer, Detector and HRP at 98/1/1 (mass ratio) was added. After the reaction was carried out at 37 ℃ for 45 minutes in the dark, the fluorescence was measured at an excitation wavelength of 520-550nm and an emission wavelength of 585-595nm by a spectrophotometer (Synegy HT, manufactured by Bio Tek, USA). XO activity in serum was expressed as mU/mL, and XO activity in liver was quantified using the protein concentration determined by Pierce BCA protein quantification kit and expressed as mU/mg. The results are shown in FIG. 3.

As can be seen from FIG. 2, Cyclo (Tyr-Gly) had a dose-dependent uric acid level lowering effect, and the group administered with Cyclo (Tyr-Gly)30 or 100mg/kg showed a significant difference in effect from the PO group, as well as the group administered with allopurinol. Further, as is clear from FIG. 3, the group administered with 100mg/kg of Cyclo (Tyr-Gly) inhibited the xanthine oxidase activity in the liver and serum as in the case of the group administered with 1mg/kg of allopurinol.

Test example 3 (study of serum uric acid level lowering Effect of Heat-treated Soybean peptide in hyperuricemic mouse)

The serum uric acid level lowering effect of the heat-treated soybean peptide was examined using a hyperuricemia model animal in the same manner as in test example 2. Specifically, animals were prepared in the same manner as in test example 2, and the following 5 groups were used for the study. 1) Normal group (Normal group, no oxazinic acid load); 2) PO dosing group (PO group, ofloxacin load); 3) PO + allopurinol 1mg/kg administration group (PO + AL group); 4) a PO + soybean peptide heat-treated material 2g/kg administration group; 5) PO +8 Tyr-containing cyclic dipeptide mixtures 11mg/kg (n in each group is 6-7). The administration and blood collection were performed for each group in the same manner as in test example 2, and the uric acid level in serum was measured. The results are shown in FIG. 4. Further, the 8-cyclic dipeptide mixture is a substance prepared from a synthetic product of Cyclo (Ser-Tyr), Cyclo (Tyr-Gly), Cyclo (Tyr-Tyr), Cyclo (Phe-Tyr), Cyclo (Leu-Tyr), Cyclo (Val-Tyr), Cyclo (Ile-Tyr) and Cyclo (Asn-Tyr) in an amount to be contained in a heat-treated product of soybean peptide.

Further, the following substances were used as heat-treated products of soybean peptides: soybean peptide [ HINUTE AM (trade name), manufactured by NOF ABO-TOYO-JAK.K.) was dissolved in distilled water at a concentration of 200mg/mL, heated at 132 ℃ for 3 hours, and then freeze-dried. The above-mentioned substances were subjected to LC-MS/MS to measure the cyclic dipeptide content of the heat-treated soybean peptide according to the following conditions. However, since the standard is unstable in an aqueous solution, Cyclo (Tyr-Cys) cannot be measured. The results are shown in Table 4.

[ LC-MS/MS analysis conditions ]

LC device SHIMADZU UFLC XR

A chromatographic column: agilent technologies Zorbax SB-AQ 1.8 μm 2.1X 150mm

Column temperature: 40 deg.C

Mobile phase: a: 0.1% formic acid, B: gradient analysis of methanol

Flow rate: 0.2mL/min

Sample introduction amount: 2 μ L

A detector: AB Sciex 4000Q TRAP-Turbo Spray (ESI) -Scheduled MRM (multiple reaction monitoring)

[ Table 4]

Cyclic dipeptides	Content (× 10)³ppm)
		Cyclo(Trp-Tyr)	0.10
Cyclo(Ser-Tyr)	1.06
		Cyclo(Pro-Tyr)	0.53
Cyclo(Tyr-Gly)	0.47
		Cyclo(Tyr-Tyr)	0.18
Cyclo(Phe-Tyr)	0.74
		Cyclo(Leu-Tyr)	0.92
Cyclo(Lys-Tyr)	1.25
		Cyclo(His-Tyr)	0.32
Cyclo(Ala-Tyr)	0.52
		Cyclo(Glu-Tyr)	0.22
Cyclo(Val-Tyr)	0.23
		Cyclo(Ile-Tyr)	1.02
Cyclo(Thr-Tyr)	0.73
		Cyclo(Asp-Tyr)	0.23
Cyclo(Asn-Tyr)	0.73
		Cyclo(Gln-Tyr)	0.39
Cyclo(Arg-Tyr)	1.34
		Cyclo(Met-Tyr)	0.17
Cyclo(Tyr-Cys)	Can not measure

As is clear from Table 4 and FIG. 4, the heat-treated soybean peptide product contains the cyclic dipeptide of the present invention and is excellent in the effect of lowering the blood uric acid level.

Test example 4 (examination of effective amount of Heat-treated Soybean peptide for hyperuricemia mice)

The effect of lowering serum uric acid level by the amount of the heat-treated soybean peptide was examined in the same manner as in test example 3 using a hyperuricemia model animal. Specifically, animals were prepared in the same manner as in test example 2, and were examined in the following 6 groups. 1) Normal group (Normal group, no oxazinic acid load); 2) PO dosing group (PO group, ofloxacin load); 3) PO + allopurinol 1mg/kg administration group (PO + AL group); 4) a PO + soybean peptide heat-treated product 200mg/kg administration group; 5) a PO + soybean peptide heat-treated material 400mg/kg administration group; 6) the PO + soybean peptide heat-treated product was administered at a dose of 800mg/kg (n: 5-6 in each group). The administration and blood collection were performed for each group in the same manner as in test example 2, and the uric acid level in serum was measured. The results are shown in FIG. 5.

As is clear from FIG. 5, when the heat-treated soybean peptide was administered at 800mg/kg, it was found that the peptide was effective because it had a significant difference in the uric acid level in the hyperuricemia model mouse.

The cyclic dipeptide of the present invention is a substance having a relieved feeling, which can be produced from a food-derived material and can be taken without any fear, and has an advantage different from allopurinol which is concerned about side effects. The cyclic dipeptide of the present invention has different degrees of action depending on the amount used, but shows a uric acid level lowering effect equal to or mild to that of allopurinol depending on the amount used. Since it takes a long time to reduce uric acid level and it is necessary to cope with diet therapy, it can be said that a reduced action is rather preferable from the viewpoint of daily administration.

Test example 5 (examination of solubility in Water)

The solubility in water was determined for the cyclic dipeptides shown in Table 5.

Specifically, each compound was added to normal temperature (25 ℃) distilled water (manufactured by Otsuka pharmaceutical Co., Ltd.) so that the final concentration was 5mM, and the mixture was dissolved by ultrasonic stirring for 30 minutes. As a result, the solubility of the compound completely dissolved by visual observation was regarded as "5 mM". Next, distilled water was added to the compound that did not dissolve in the 5mM concentration so that the final concentration was 1mM, and the compound was dissolved by stirring under ultrasonic waves for 30 minutes. As a result, the dissolved compound was labeled as "1 mM" in solubility. And to 1mM concentration of the compounds without dissolved by adding distilled water, so that the final concentration of 0.1mM, then ultrasonic stirring for 30 minutes, confirmed the solubility but not dissolved compounds, even if adding distilled water to the final concentration of 0.01mM, then ultrasonic stirring for 30 minutes, also did not dissolve compounds. The solubility "insoluble" is stated for the above compounds. The results are shown in Table 5.

[ Table 5]

Cyclic dipeptides	Solubility in water
		Cyclo(Trp-Tyr)	Insoluble matter
Cyclo(Ser-Tyr)	Insoluble matter
		Cyclo(Pro-Tyr)	1mM
Cyclo(Tyr-Gly)	1mM
		Cyclo(Tyr-Tyr)	Insoluble matter
Cyclo(Phe-Tyr)	Insoluble matter
		Cyclo(Leu-Tyr)	Insoluble matter
Cyclo(Lys-Tyr)	5mM
		Cyclo(His-Tyr)	1mM
Cyclo(Ala-Tyr)	Insoluble matter
		Cyclo(Glu-Tyr)	5mM
Cyclo(Val-Tyr)	Insoluble matter
		Cyclo(Ile-Tyr)	1mM
Cyclo(Thr-Tyr)	1nM
		Cyclo(Asp-Tyr)	5mM
Cyclo(Asn-Tyr)	1mM
		Cyclo(Gln-Tyr)	1mM
Cyclo(Arg-Tyr)	5mM
		Cyclo(Met-Tyr)	5mM

The solubility in water of Cyclo (Pro-Tyr), Cyclo (Tyr-Gly), Cyclo (Lys-Tyr), Cyclo (His-Tyr), Cyclo (Glu-Tyr), Cyclo (Ile-Tyr), Cyclo (Thr-Tyr), Cyclo (Asp-Tyr), Cyclo (Asn-Tyr), Cyclo (Gln-Tyr), Cyclo (Arg-Tyr) and Cyclo (Met-Tyr) is high, and among them, Cyclo (Lys-Tyr), Cyclo (Glu-Tyr), Cyclo (Asp-Tyr), Cyclo (Arg-Tyr) and Cyclo (Met-Tyr) have a solubility in water of 5mM or more, and can be preferably used for the preparation of the composition.

Specific formulations of the compositions containing the cyclic dipeptides or their salts of the present invention are shown below. These compositions can be prepared according to known methods.

(production example) production of carbonated beverage

Cyclic dipeptides synthesized by japan shenhu natural products chemical company were used, and the raw materials in the ratios shown in table 6 below were dissolved in water, the pH was adjusted to 3.8 with phosphoric acid, and appropriate amounts of an antioxidant, a flavor, an acidulant, a sweetener, and a caramel color were added, and then stored for about 24 hours. During the preparation, proper amount of carbon dioxide is added, and the mixture is filtered, bottled and sterilized (heating at 65 deg.C for 10 min) to obtain carbonated beverage.

[ Table 6]

(production example) production example of chocolate

Chocolate was produced using the raw materials in the ratios shown in table 7 below. The raw materials of table 7 were put into a Hobart mixer, mixed at medium speed for 3 minutes, and subjected to roll milling, mixing and stirring to obtain chocolate dough. The chocolate mass is tempered (Tempering), poured into molds and cooled to produce the chocolate of the present invention.

[ Table 7]

Production example of beer-flavored carbonated beverage

Cyclic dipeptides synthesized by japan shenhu natural products chemical company were dissolved in water in the following raw materials in the ratios shown in table 8, the pH was adjusted to 3.7 with lactic acid, and appropriate amounts of an antioxidant, a flavor, an acidulant, a sweetener, a bitterant, and a caramel color were added, and then stored for about 24 hours. During the preparation, carbon dioxide is added in a proper amount, and then the beer-flavored carbonated beverage is prepared through the processes of filtering, bottling and sterilizing (heating at the temperature of more than 65 ℃ for 10 minutes).

[ Table 8]

Industrial applicability

The cyclic dipeptide-containing composition of the present invention is a substance having an excellent effect of lowering uric acid level, and is useful for the prevention or treatment of hyperuricemia, gout, and the like.

Claims

1. A cyclic dipeptide-containing composition characterized by containing 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof in amounts satisfying the respective ranges of amounts as described in (1) to (8),

2. The composition according to claim 1, further comprising 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof which are described in the following (9) to (19) in an amount satisfying the respective ranges of the amounts,

(9) the content of the cyclotryptophanyl tyrosine or the salt thereof is 0.08 × 10-0.12 × 10⁵ppm

(10) The content of the cyclic seryl tyrosine or the salt thereof is 0.80 × 10-1.30 × 10⁵ppm

(11) The content of the cyclo-prolyl tyrosine or the salt thereof is 0.40 × 10-0.70 × 10⁵ppm

(12) The content of cyclotyrosylglycine or a salt thereof is 0.30 × 10-0.60 × 10⁵ppm

(13) The content of the cyclotyrosyl tyrosine or the salt thereof is 0.10 × 10-0.30 × 10⁵ppm

(14) The content of the cyclophenylalanyl tyrosine or the salt thereof is 0.50 × 10-0.90 × 10⁵ppm

(15) The content of the cyclamenyl tyrosine or the salt thereof is 0.70 × 10-1.10 × 10⁵ppm

(16) The content of cyclyl group aminoacyl tyrosine or its salt is 0.20 × 10-0.40 × 10⁵ppm

(17) The content of the alanyl-tyrosine or the salt thereof is 0.40 × 10-0.70 × 10⁵ppm

(18) The content of the cyclic glutamyl tyrosine or the salt thereof is 0.10 × 10-0.30 × 10⁵ppm

(19) The content of the cyclic valyl tyrosine or the salt thereof is 0.10 × 10-0.30×10⁵ppm。

3. The composition according to claim 1 or 2, wherein the total amount of the tyrosine-containing cyclic dipeptide or salt thereof is 8.0 × 10 to 1.0 × 10⁶ppm。

4. A cyclic dipeptide-containing composition characterized by containing 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof in amounts satisfying the respective ranges of amounts as described in (1) to (8),

5. The composition according to claim 4, further comprising 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof which are described in the following (9) to (19) in an amount satisfying the respective ranges of the amounts,

(9) the content of cyclotryptophanyl tyrosine or its salt is 0.4 × 10^-4～0.7×10mg/100mL

(10) The content of cycloserinyl tyrosine or its salt is 4.0 × 10^-4～8.0×10mg/100mL

(11) Cyclic prolineContent of acyl tyrosine or its salt 2.0 × 10^-4～4.0×10mg/100mL

(12) The content of cyclotyrosylglycine or its salt is 2.0 × 10^-4～4.0×10mg/100mL

(13) The content of cyclotyrosyl tyrosine or its salt is 0.8 × 10^-4～2.0×10mg/100mL

(14) The content of cyclophenylalanyl tyrosine or its salt is 3.0 × 10^-4～5.0×10mg/100mL

(15) The content of the cyclleucyl tyrosine or the salt thereof is 4.0 × 10^-4～7.0×10mg/100mL

(16) Content of cyclyl-tyrosines or salts thereof 1.0 × 10^-4～3.0×10mg/100mL

(17) The content of the alanyl tyrosine or the salt thereof is 2.0 × 10^-4～4.0×10mg/100mL

(18) The content of the cyclic glutamyl tyrosine or its salt is 1.0 × 10^-4～2.0×10mg/100mL

(19) The content of Cyclovalyl tyrosine or its salt is 1.0 × 10^-4～2.0×10mg/100mL。

6. The composition according to claim 4 or 5, wherein the total amount of tyrosine-containing cyclic dipeptide or salt thereof is 5.0 × 10^-3～8.0×10²mg/100mL。

7. A cyclic dipeptide-containing composition characterized by containing 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof in amounts satisfying the respective ranges of amounts as described in (1) to (8),

(1) content of cycllysyltyrosine or a salt thereof: 0.01 to 15% by weight

(7) Content of cyclarginyl tyrosine or a salt thereof: 0.01 to 16% by weight

(8) Content of cyclomethionyl tyrosine or a salt thereof: 0.001 to 2% by weight.

8. The composition according to claim 7, further comprising 1 or 2 or more tyrosine-containing cyclic dipeptides or salts thereof which are described in (9) to (19) below in amounts satisfying the respective ranges of amounts,

(9) content of cyclotryptophanyl tyrosine or a salt thereof: 0.0008 to 1.2% by weight

(10) Content of cyclic seryl tyrosine or a salt thereof: 0.008 to 13% by weight

(11) Content of ring prolyl tyrosine or a salt thereof: 0.004 to 7% by weight

(12) Content of cyclotyrosylglycine or a salt thereof: 0.003 to 6% by weight

(13) Content of cyclotyrosyl tyrosine or a salt thereof: 0.001 to 3% by weight

(14) Content of cyclophenylalanyl tyrosine or a salt thereof: 0.005 to 9% by weight

(15) Content of cyclleucyltyrosine or a salt thereof: 0.007 to 11% by weight

(16) Content of cyclyl aminoacyl tyrosine or salt thereof: 0.002-4 wt%

(17) Content of cyclopropyltyrosine or a salt thereof: 0.004 to 7% by weight

(18) Content of cyclic glutamyl tyrosine or a salt thereof: 0.001 to 3% by weight

(19) Content of cyclovalyl tyrosine or a salt thereof: 0.001 to 3% by weight.

9. The composition according to claim 7 or 8, wherein the total amount of the tyrosine-containing cyclic dipeptide or salt thereof is 0.008 to 100 wt.%.

10. The composition according to any one of claims 1 to 9, wherein the composition containing the tyrosine-containing cyclic dipeptide is a treated product obtained by heat-treating a solution containing a soybean peptide.