Amino acid mixtures with co-amorphous structures

Abstract

The present invention provides a means for increasing the solubility of even a poorly soluble amino acid without changing to an expensive peptide and also without changing the pH, and is characterized in that at least two kinds of amino acids have a coamorphous structure.

Description

[Technical field]

[0001] The present invention relates to an amino acid mixture having a co-amorphous structure and a method for producing the same. [Background technology]

[0002] Among foods that supply amino acids, various efforts have been made to dissolve poorly soluble amino acids to a desired concentration in beverages that are dissolved in water and consumed, and in high-calorie infusion solutions that contain amino acids.

[0003] Japanese Patent Publication No. 7-64741 discloses highly soluble dipeptides containing amino acids that are desired to be ingested, such as L-aspartyl-L-leucine and L-aspartyl-L-tyrosine. The dipeptides are hydrolyzed into amino acids in the body and absorbed.

[0004] Japanese Patent No. 3368897 discloses a liquid preparation in which three branched-chain amino acids consisting of isoleucine, leucine, and valine are dissolved in a certain mass ratio in water at a pH of 4.5 to 2.2 in the presence of an organic acid and / or an inorganic acid. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Tokuhei 7-64741 [Patent Document 2] Patent No. 3368897 Summary of the Invention [Problem to be solved by the invention]

[0006] The method of producing peptides from amino acids has a higher product cost than amino acids. In addition, the method of adjusting pH with organic acids cannot be used for products that use compounds that are unstable in that pH range, and the poorly soluble amino acids must be dissolved separately, so their applications are sometimes limited.

[0007] An object of the present invention is to provide a means for increasing the solubility of amino acids without using expensive peptides or changing the pH. [Means for solving the problem]

[0008] The present invention has been made to solve the above-mentioned problems, and was made based on the discovery that when two or more amino acids are combined to form an amorphous structure, the co-amorphous structure of both amino acids is stably maintained.

[0009] That is, the present invention provides an amino acid mixture having a co-amorphous structure, in which at least two of a plurality of amino acids have a co-amorphous structure, the plurality of amino acids including amino acid 1 represented by R1-CH(NH2)COOH and amino acid 2 represented by R2-CH(NH2)COOH, where R1 and R2 are each selected from the group consisting of a hydrogen group, an alkyl group having 1 to 5 carbon atoms, and a hydroxyl group, an amino group, a carboxyl group, an aromatic ring, a sulfide bond, a disulfide bond, a thiol group, and a group having a cyclic structure.

[0010] The amino acids forming the co-amorphous structure are usually composed of the above-mentioned amino acid 1 and amino acid 2. Therefore, the present invention provides an amino acid mixture having a co-amorphous structure, in which amino acid 1 and amino acid 2 form a co-amorphous structure, amino acid 1 is represented by R1-CH(NH2)COOH, and amino acid 2 is represented by R2-CH(NH2)COOH, and R1 and R2 each contain at least one selected from the group consisting of a hydrogen group, an alkyl group having 1 to 5 carbon atoms, and a hydroxyl group, an amino group, a carboxyl group, an aromatic ring, a sulfide bond, a disulfide bond, a thiol group, and / or a group containing a cyclic structure.

[0011] Normally, amino acid crystals have a substance-specific lattice energy and a solubility specific to the crystal. However, since the co-amorphous structure is not a crystal, the lattice energy is lowered, which increases the amount of dissolution. Since the amino acid 1 and amino acid 2 of the present invention have a co-amorphous structure, the amount of dissolution has been successfully increased.

[0012] The amino acids used in the present invention usually exist as crystals. This is because these simple amorphous substances are unstable and will transition to crystals if left alone. In crystals, molecules are regularly arranged to form a crystal lattice. On the other hand, amorphous substances do not have the long-range order of a crystal lattice, and have very low interactions that stabilize the solid state, such as lattice energy, so they are more easily dispersed and hydrated than crystals, and have a faster dissolution rate.

[0013] Although the present invention is not bound by any theory, the co-amorphous structure is structurally unstable compared to a crystal, and has a low lattice energy, so it is more likely to dissolve. This is generally recognized in the pharmaceutical industry, where the solubility of a crystal is called kinetic solubility, and the solubility of an amorphous structure is called thermodynamic solubility. Furthermore, the reason why the co-amorphous structure is stable at a higher supernatant amino acid concentration than a crystal is that the co-amorphous structure takes a longer time to precipitate as a crystal than a crystal. When a crystal dissolves, it forms an association that maintains a crystalline structure in water, while the co-amorphous structure does not have a crystalline structure and therefore forms a completely random association in water. It is necessary to transition from a random association to an association with a crystalline structure, and this transition takes a long time.

[0014] Meanwhile, regarding amino acids, solid solutions of three kinds of amino acids, valine, leucine, and isoleucine, are also known (WO2010 / 050168), and it is also known that the dissolution rate of valine, leucine, and isoleucine in this solid solution is improved. However, in a solid solution, a part of the crystal lattice is replaced by other molecules, or other molecules are inserted between the crystal lattices, that is, it is a crystal and does not have a random structure like an amorphous body. The dissolution rate of the solid solution is much slower than that of the co-amorphous structure of the present invention. Effect of the Invention

[0015] The amino acid mixture of the present invention is highly stable, and can increase solubility without using expensive peptides, and can easily dissolve even poorly soluble amino acids. In addition, it can stably maintain an amorphous structure with a high energy state, which has the advantage of increasing the absorbability of the amino acid or developing new uses. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is a powder X-ray spectrum showing that Tyr-Arg is co-amorphous. [Diagram 2] 1 is a graph showing the results of a dissolution test of a Tyr-Arg co-amorphous material. [Diagram 3] Powder X-ray spectra in a storage stability test of the Tyr-Arg co-amorphous body. [Figure 4] FIG. 1 shows powder X-ray spectrum diagrams of Tyr and various amino acids. [Diagram 5] 1 is a graph showing the results of a dissolution test of Tyr-LysH co-amorphous material and Tyr crystals. [Figure 6] FIG. 1 shows powder X-ray spectrum of Cys2-Arg and Cys2 alone. [Figure 7] FIG. 1 shows powder X-ray spectrum diagrams of combinations of Cys2 and various amino acids. [Figure 8] FIG. 1 is a powder X-ray spectrum diagram of a combination of various amino acids including Leu. [Figure 9] FIG. 1 shows powder X-ray spectrum diagrams of Met-LysH, Met-Arg and Met alone. [Figure 10] FIG. 1 shows powder X-ray spectrum diagrams of Tyr-Arg obtained by changing the grinding time. [Figure 11] FIG. 1 shows powder X-ray spectrum diagrams of Tyr-Arg and Tyr alone obtained using a spray dryer. [Figure 12] FIG. 1 shows the powder X-ray spectrum of freeze-dried Tyr-Arg and Leu-Arg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The amino acids that form the co-amorphous structure of the present invention are not limited to α-amino acids, but may be β-amino acids such as β-alanine, γ-amino acids such as γ-aminobutyric acid, δ-amino acids, and the like.

[0018] However, typically, amino acid 1 and amino acid 2 form a co-amorphous structure. Amino acid 1 is represented by R1-CH(NH2)COOH, and amino acid 2 is represented by R2-CH(NH2)COOH, both of which are α-amino acids. R1 and R2 each contain at least one group selected from the group consisting of a hydrogen group, an alkyl group having 1 to 5 carbon atoms, and a hydroxyl group, an amino group, a carboxyl group, an aromatic ring, a sulfide bond, a disulfide bond, a thiol group, and / or a group containing a cyclic structure.

[0019] The amino acid in which R1 or R2 is a hydrogen group is glycine, and the amino acid in which R1 or R2 is an alkyl group having 1 to 5 carbon atoms is alanine, valine, leucine, isoleucine, etc. The amino acid containing a hydroxyl group is serine, threonine, etc., the amino acid containing an amino group is lysine, arginine, ornithine, glutamine, asparagine, etc., and the amino acid containing a carboxyl group is aspartic acid, glutamic acid, etc. The amino acid containing an aromatic ring is phenylalanine, tyrosine, etc., the amino acid containing a sulfide or disulfide bond is methionine, cystine, etc., and the amino acid containing a thiol group is cysteine, etc. The amino acid containing a cyclic structure is one containing a heterocycle such as histidine, tryptophan, proline, hydroxyproline, etc. Imino acids such as proline and hydroxyproline are also included in the amino acid 1 or amino acid 2 of the present invention.

[0020] These amino acids have different degrees of ease in forming a co-amorphous structure, and it is preferable to combine at least one amino acid that is likely to form a co-amorphous structure with the other amino acid. The amino acids that are likely to form a co-amorphous structure are basic amino acids that contain an amino group or an imide bond in R1 or R2, such as lysine, arginine, ornithine, histidine, and salts thereof, and sulfur-containing amino acids that contain a sulfide or disulfide bond or a thiol group in R1 or R2, such as cysteine, cystine, and methionine.

[0021] One of the objects of the present invention is to easily dissolve poorly soluble amino acids, and poorly soluble amino acids are cystine, tyrosine, phenylalanine, leucine, isoleucine, tryptophan, valine, methionine, etc. The amino acid to be combined with the poorly soluble amino acid is not particularly limited as long as it forms a co-amorphous structure, and may also be a poorly soluble amino acid, for example. Examples of the amino acid to be combined with the poorly soluble amino acid include alanine, valine, leucine, isoleucine, lysine, arginine, histidine, ornithine, glutamine, asparagine, aspartic acid, glutamic acid, serine, etc., and preferably arginine, lysine, histidine, and cystine.

[0022] Particularly preferred combinations are tyrosine and arginine, tyrosine and serine, tyrosine and lysine hydrochloride, tyrosine and histidine, cystine and arginine, cystine and serine, cystine and monosodium glutamate monohydrate, cystine and hydroxyproline, cystine and histidine, cystine and gamma-aminobutyric acid, leucine and arginine, leucine and lysine hydrochloride, leucine and histidine, leucine and cystine, isoleucine and arginine, isoleucine and lysine hydrochloride, isoleucine and histidine, isoleucine and cystine, valine and arginine, valine and lysine hydrochloride, valine and histidine, valine and cystine, methionine and arginine, and methionine and lysine hydrochloride.

[0023] The combination of amino acids can be selected based on the intended use, and can be selected from combinations of amino acids that have been used for that intended use. The number of amino acids is not limited to two, and three or more amino acids that form a co-amorphous structure can be combined.

[0024] The mixing ratio of amino acids in the amino acid mixture having a co-amorphous structure of the present invention may be any ratio that allows the formation of a co-amorphous structure. For example, in the case of two types of amino acids, the molar ratio may be 1:0.1 to 1:10, preferably 1:0.2 to 1:5, preferably 1:0.5 to 1:2, more preferably 1:0.6 to 1:2, even more preferably 6:4 to 4:6, and most preferably a molar ratio of 1:1.

[0025] The co-amorphous structure of the present invention is a structure in which two or more amino acids are all stably maintained in an amorphous state, and each is uniformly dispersed and mixed. Although each amino acid is solid, the degree of dispersion of each amino acid differs depending on the manufacturing method. That is, if a method of dissolving and solidifying each amino acid, such as a spray-drying method, a melt quenching method (hot melt method), or a freeze-drying method is used, each amino acid will be in a solidified solution, that is, in a state where they are mixed in molecular units, and if a method of mixing and grinding them as powder, such as a ball mill method, is used, they will be in a state where fine powders are mixed. Even in this case, it is thought that each amino acid molecule is in a state where it can interfere with each other, and is in an extremely fine state (median diameter is about 5 to 30 μm).

[0026] Whether or not each amino acid has a co-amorphous structure can be confirmed by known methods, such as X-ray diffraction and Raman spectroscopy.

[0027] The amino acid mixture of the present invention is sufficient if at least two amino acids are in a co-amorphous structure, but may also be in a co-amorphous structure of three or more amino acids including other amino acids. In addition, the mixture may contain other amino acids that are not in a co-amorphous structure with the at least two amino acids in the co-amorphous structure, or a third component other than the amino acids that may or may not be in a co-amorphous structure, an amino acid salt, or other components.

[0028] The amino acid co-amorphous structure of the present invention can be produced by, for example, a ball mill grinding method, a spray drying method, a melt quenching method, a freeze drying method, or the like.

[0029] For the ball mill, for example, a ball mill Emax manufactured by Verder Scientific can be used. In the method using this ball mill, each amino acid is charged in a predetermined mixing ratio, and a grinding aid is added as necessary, and the mixture is ground and mixed until a co-amorphous structure is formed. Each amino acid to be charged may be either crystalline or amorphous, but is usually crystalline. The grinding aid is added to prevent each amino acid from caking during grinding, and ethanol, etc. may be added in an amount of about 0.1 to 5 mass%, preferably about 1 to 3 mass%, based on the total amount of all amino acids. The grinding conditions are until the crystal lattice of each amino acid is broken and at least two kinds of amino acids form a co-amorphous structure, and usually, the ball mill rotation speed is 200 to 1200 rpm for about 15 minutes to 12 hours, preferably 600 to 1200 rpm for 8 to 12 hours, and more preferably 800 to 1200 rpm for 12 hours or more. Since the temperature of the ball mill rises during grinding, it is recommended to cool the pot of the ball mill to 15°C or less, preferably 5 to 12°C. Grinding aids such as ethanol volatilize during grinding and do not remain in the mixture. In addition, a planetary ball mill (Kurimoto Iron Works, Ltd.), an attritor (Nippon Coke and Engineering Co., Ltd.), or a surface modification device, Shimo-Royer (Zoz GmbH), can also be used as a ball mill.

[0030] In the case of production by spray drying, an aqueous solution containing each amino acid in a predetermined mixing ratio is prepared and spray-dried, preferably at a temperature of 160° C. or higher. It is desirable to evaporate the water before the crystal lattice is formed.

[0031] The amino acid mixture having a co-amorphous structure of the present invention can be widely used in foods and beverages, such as nutritional supplement drops and health foods, as well as in medicines and cosmetics. In particular, it can be used as a substitute for nutritional supplement drops that have been conventionally made into dipeptides such as L-aspartyl-L-leucine and L-aspartyl-L-tyrosine by adjusting the pH in the form of a salt with an organic acid. The amino acid combination can be preferably selected from amino acids used for each purpose. EXAMPLES

[0032] Example 1 (1) Preparation of Tyr·Arg co-amorphous mixture 5.1g (0.028mol) of tyrosine (Tyr) (Ajinomoto Co., Ltd.), 4.9g (0.028mol) of arginine (Arg) (Ajinomoto Co., Ltd.), and 0.1mL of ethanol as a grinding aid were placed in a 125mL pot made of zirconia. 50 10mm zirconia balls were placed in the pot and set in a ball mill (Verder Scientific, Retsch Emax). The mixture was ground and mixed for 12 hours at a grinding temperature of approximately 28℃ while running 15℃ cooling water around the periphery of the pot at a rotation speed of 1000rpm, and 9.5g of powder was obtained.

[0033] (2) Experiment to confirm amorphization The powder X-ray diffraction pattern of the solid obtained in (1) was obtained using a powder X-ray diffractometer (Malvern Panalytical, Empyrean). The results are shown in Figure 1. In the figure, line a represents the ground mixture ground for 0 hours, line b represents the ground mixture ground for 4 hours, and line c represents the ground mixture ground for 12 hours. As a result, no clear peaks characteristic of a crystal structure were confirmed. This confirmed that the solid obtained in (1) was amorphous.

[0034] (3) Dissolution amount confirmation test Four 200 mL glass sample bottles (A, B, C, D) were filled with 100 mL of ultrapure water and 138 mg, 138 mg, 220 mg, and 220 mg of the solid obtained in (1) in order from A, and each was stirred using a magnetic stirrer (As One Corporation B-1 Magnetic Stirrer Octopus). After the powder was completely dissolved, the pH was adjusted to a range of 6.5 to 7.5 using 5 mol / L hydrochloric acid. A to D were immersed in a 25 °C water bath (Tokyo Rikakikai Co., Ltd. NCB-3300), A and C were stirred with a magnetic stirrer, and B and D were left to stand. After 2 hours, 2 mL was sampled from each sample bottle and filtered using a 0.45 μm filter (Merck Millex). The filtered sample was diluted 50 times and the Tyr concentration in the supernatant was quantified using high performance liquid chromatography (HPLC) (Agilent 1100 Series).

[0035] The same operation was performed after 24 hours, 48 ​​hours, and 333 hours. The results are shown in Figure 2. In the figure, ○ indicates A (stirring, 138 mg), △ indicates B (standing, 138 mg), ● indicates C (stirring, 220 mg), and ▲ indicates D (standing, 220 mg). As a result, in A and B, no decrease in the supernatant concentration was confirmed, and it was confirmed that the Tyr concentration was maintained at 630 mg / L. On the other hand, in both C and D, crystal precipitation was confirmed, and it was confirmed that the supernatant Tyr concentration decreased. From this, it was confirmed that when the solid obtained in (1) was dissolved, the Tyr concentration in the supernatant was maintained at 630 mg / L for 333 hours, regardless of the stirring or standing conditions (A, B).

[0036] (4) Stability testing The solid obtained in (1) was placed in an aluminum pouch, silica gel was added, and the pouch was stored in a refrigerator at 4°C in a dehumidified environment. After 7 days and 16 days, the powder X-ray diffraction pattern of the solid (Figure 3) was obtained using a powder X-ray diffractometer. As a result, no clear peaks characteristic of a crystalline structure were confirmed. This confirmed that the amorphous structure of the solid obtained in (1) was maintained for 16 days.

[0037] Examples 2 to 4, Comparative Examples 1 to 6 (1) Preparation of Tyr / amino acid co-amorphous mixture Each amino acid shown in Table 1 was used, and the amino acids were ground in the same manner as in Example 1, except that the grinding temperature was 30°C.

[0038] [Table 1]

[0039] (2) Experiment to confirm amorphization The solid obtained in (1) was measured using the same powder X-ray diffractometer as in Example 1, and the powder X-ray diffraction pattern is shown in Figure 4. From the powder X-ray diffraction pattern, it was confirmed that Tyr-Ser, Tyr-LysH, and Tyr-His were co-amorphized. The confirmation results are shown in Table 1.

[0040] (3) Dissolution amount confirmation test Two 200 mL glass sample bottles (A, B) were filled with 100 mL of ultrapure water and 138 mg each of the solid and Tyr crystals from Example 3, and each was stirred using a magnetic stirrer (B-1 Magnetic Stirrer Octopus, AS ONE Corporation). After the powder was completely dissolved, the pH was adjusted to a range of 6.5 to 7.5 using 5 mol / L hydrochloric acid. The sample bottles were immersed in a 25°C water bath (NCB-3300, Tokyo Rikakikai Co., Ltd.) and stirred using a magnetic stirrer.

[0041] 2 mL of each sample bottle was sampled 5, 10, 30 min, 1 h, 2 h, 24 h, and 168 h after the start of stirring, and filtered using a 0.45 μm filter (Merck Millex). The filtered samples were diluted 50-fold and the Tyr concentration in the supernatant was quantified using high performance liquid chromatography (HPLC) (Agilent 1100 Series).

[0042] The results are shown in Figure 5. It was confirmed that when Example 3 obtained in (1) was dissolved, 600 mg / L of Tyr crystals was dissolved in 30 minutes and maintained for 168 hours, as compared with the result that 430 mg / L of Tyr crystals was dissolved in 24 hours.

[0043] Example 5, Comparative Example 7 (1) Preparation of Cys2·Arg co-amorphous mixture Cystine (Cys2) (Ajinomoto Co., Inc.) 6.76 g (0.0282 mol) and arginine (Arg) (Ajinomoto Co., Inc.) 3.24 g (0.0186 mol) were used, and the amino acids were ground in the same manner as in Example 1, except that the grinding temperature was set to 30° C. In addition, 10 g of the same cystine was used, and the amino acid was ground in the same manner.

[0044] (2) Experiment to confirm amorphization The solid obtained in (1) was measured using the same powder X-ray diffractometer as in Example 1 to obtain a powder X-ray diffraction pattern.

[0045] The results are shown in Figure 6. In the figure, "before" indicates the state before grinding, and "after" indicates the state after grinding. From the results in Figure 6, it was confirmed that Cys2·Arg after grinding was amorphous, with no clear peaks characteristic of a crystal structure being observed. On the other hand, in the case of Cys2 alone, crystallinity remained.

[0046] Examples 6 to 12 (1) Preparation of Cys2 / amino acid 2 co-amorphous mixture Each amino acid shown in Table 2 was used, and the amino acids were ground in the same manner as in Example 1, except that the grinding temperature was 30° C. and the grinding time was 30 minutes.

[0047] [Table 2]

[0048] (2) Experiment to confirm amorphization The solid obtained in (1) was measured using the same powder X-ray diffractometer as in Example 1, and the powder X-ray diffraction pattern is shown in Figure 7. From the powder X-ray diffraction pattern, it was confirmed that Cys2-Arg, Cys2-Ser, Cys2-MSG, Cys2-HyPro, Cys2-His, Cys2-LysH, and Cys2-GABA were co-amorphized. The results are shown in Table 2.

[0049] Examples 13 to 15, Comparative Examples 8 to 11 (1) Preparation of Amino Acid 1 / Amino Acid 2 Co-Amorphous Mixture The amino acids shown in Table 3 were used, and the amino acids were ground in the same manner as in Example 1, except that the grinding temperature was 30° C. and the grinding time was 6 hours.

[0050] [Table 3]

[0051] (2) Experiment to confirm amorphization The solid obtained in (1) was measured using the same powder X-ray diffractometer as in Example 1, and the powder X-ray diffraction pattern is shown in Figure 8. From the powder X-ray diffraction pattern, it was confirmed that Leu-Arg, Val-Arg, and Ile-Arg were co-amorphized. The confirmation results are shown in Table 3.

[0052] Examples 16 and 17 (1) Preparation of Amino Acid 1 / Amino Acid 2 Co-Amorphous Mixture The amino acids shown in Table 4 were used, and the amino acids were ground in the same manner as in Example 1, except that the grinding temperature was 30°C.

[0053] [Table 4]

[0054] (2) Experiment to confirm amorphization The solid obtained in (1) was measured using the same powder X-ray diffractometer as in Example 1, and the powder X-ray diffraction pattern is shown in Figure 9. From the powder X-ray diffraction pattern, it was confirmed that Met-Arg and Met-Lys were co-amorphized. The confirmation results are shown in Table 4.

[0055] Examples 18 to 21 For tyrosine and arginine, the amino acids were ground in the same manner as in Example 1, except that the rotation speed was adjusted to the value shown in Table 5. The results of confirming co-amorphization are shown in Table 5.

[0056] [Table 5]

[0057] Example 22 For tyrosine and arginine, the amino acids were ground in the same manner as in Example 1, except that the grinding time was adjusted to that shown in Table 6. The results of confirming co-amorphization are shown in Table 6 and FIG.

[0058] [Table 6]

[0059] Example 23: Planetary Ball Mill 20.4g (0.11mol) of tyrosine (Tyr) (Ajinomoto Co., Inc.), 19.6g (0.11mol) of arginine (Arg) (Ajinomoto Co., Inc.), and 2mL of ethanol as a grinding aid were placed in a 500mL zirconia pot. 456g of 20mm zirconia balls were placed in the pot and set in a planetary ball mill (Kurimoto Iron Works, Ltd., BX382). Nitrogen gas was sealed in the pot, and grinding and mixing were performed for 5 hours at 382rpm revolution and 842rpm rotation, obtaining 37.7g of co-amorphous powder. During this time, the temperature rose from room temperature to a maximum of 60°C.

[0060] Example 24: Attritor 143g (0.79mol) of tyrosine (Tyr) (Ajinomoto Co., Ltd.), 137g (0.79mol) of arginine (Arg) (Ajinomoto Co., Ltd.), and 4mL of ethanol as a grinding aid were placed in a stainless steel vessel. 11.9kg of 15mm zirconia balls were placed in the pot and set in an attritor (MA1D, Nippon Coke and Engineering Co., Ltd.). Nitrogen gas was sealed in the vessel, and the arm was rotated at 300rpm while running tap water around the periphery of the pot for 4 hours to obtain 250g of co-amorphous powder.

[0061] Example 25: Surface modification device (Shimo-Year) 102g (0.56mol) of tyrosine (Tyr) (Ajinomoto Co., Ltd.), 98g (0.56mol) of arginine (Arg) (Ajinomoto Co., Ltd.), and 4mL of ethanol as a grinding aid were placed in a 2L vessel made of alumina. 2kg of 5mm zirconia balls were placed in the pot and set in a surface modification device (Zoz GmBH, CM-01). The arm was rotated at 1000rpm, and 10℃ cooling water was poured around the periphery of the pot. The mixture was ground and mixed for 3 hours, yielding 184g of co-amorphous powder.

[0062] Example 26: Spray Dryer 3.60 g of tyrosine crystals and 3.46 g of arginine were dissolved in 12 L of water. The solution of tyrosine and arginine was spray-dried using a spray dryer (GB210 manufactured by Yamato Scientific Co., Ltd.) at an air volume of 0.51 m3 / min, an inlet temperature of 180 to 190°C, an outlet temperature of 60°C, an atomizer gas pressure of 0.13 MPa, and a liquid delivery rate of 20 mL / min to obtain 520 mg of crystals. Powder X-ray diffraction spectrum confirmed that the crystals were co-amorphized. The powder X-ray diffraction pattern is shown in Figure 11.

[0063] Example 27 500 mg of leucine and 664 mg of arginine were dissolved in 100 mL of water and frozen in a -80°C freezer. Using a freeze dryer (Tokyo Rikakikai Co., Ltd. FDU-1200), vacuum drying was performed at a temperature of -45°C and a vacuum degree of 21 Pa for 4 days, yielding 1013 mg of powder (87% yield). The powder X-ray diffraction pattern of the obtained powder is shown in Figure 12. From the powder X-ray diffraction analysis, it seems that the co-amorphization has progressed, but it has not yet become completely co-amorphous.

[0064] Example 28 300 mg of tyrosine and 288 mg of arginine were dissolved in 100 mL of water and frozen in a -80°C freezer. Using a freeze dryer (Tokyo Rikakikai Co., Ltd. FDU-1200), vacuum drying was performed at a temperature of -45°C and a vacuum degree of 21 Pa for 4 days, yielding 419 mg of powder (71% yield). The powder X-ray diffraction pattern of the obtained powder is shown in Figure 12. From the powder X-ray diffraction analysis, it seems that the co-amorphization has progressed, but it has not yet become completely co-amorphous. [Industrial Applicability]

[0065] The present invention can be widely used in fields such as multiple media, foods, and pharmaceuticals that use two or more amino acids, and is particularly effective in applications that involve dissolving poorly soluble amino acids.

Claims

1. At least amino acid 1 and amino acid 2 among the plurality of amino acids have a co-amorphous structure; Amino Acid 1 and Amino Acid 2 are different and each independently selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, lysine, arginine, ornithine, glutamine, asparagine, aspartic acid, glutamic acid, phenylalanine, tyrosine, methionine, cystine, cysteine, histidine, tryptophan, proline, and hydroxyproline; At least one of the amino acid 1 and the amino acid 2 is selected from the group consisting of cystine, tyrosine, phenylalanine, leucine, isoleucine, tryptophan, valine, and methionine. An amino acid mixture having a co-amorphous structure (excluding the amino acid mixtures in which each of the combinations shown in Combinations 1 to 4 below results in a co-amorphous structure). Pair 1: Tryptophan and Proline Combination 2: Phenylalanine and Tryptophan Combination 3: Arginine and Phenylalanine Combo 4: Arginine and Tryptophan

2. Amino acid 1 and amino acid 2 are in a co-amorphous structure. Amino Acid 1 and Amino Acid 2 are different and each independently selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, lysine, arginine, ornithine, glutamine, asparagine, aspartic acid, glutamic acid, phenylalanine, tyrosine, methionine, cystine, cysteine, histidine, tryptophan, proline, and hydroxyproline; At least one of the amino acid 1 and the amino acid 2 is selected from the group consisting of cystine, tyrosine, phenylalanine, leucine, isoleucine, tryptophan, valine, and methionine. An amino acid mixture having a co-amorphous structure (excluding the amino acid mixtures in which each of the combinations shown in Combinations 1 to 4 below results in a co-amorphous structure). Pair 1: Tryptophan and Proline Combination 2: Phenylalanine and Tryptophan Combination 3: Arginine and Phenylalanine Combo 4: Arginine and Tryptophan

3. 3. The amino acid mixture according to claim 1 or 2, wherein one of said amino acid 1 and said amino acid 2 is an amino acid selected from the group consisting of lysine, arginine, histidine, cystine, methionine, cysteine, and salts thereof.

4. 4. The amino acid mixture according to claim 1, wherein one of said amino acid 1 and said amino acid 2 is cystine, tyrosine, phenylalanine, leucine, isoleucine or tryptophan.

5. 5. The amino acid mixture according to claim 1, wherein the amino acids forming the co-amorphous structure are selected from the group consisting of tyrosine and arginine, tyrosine and serine, tyrosine and lysine hydrochloride, tyrosine and histidine, cystine and arginine, cystine and serine, cystine and sodium glutamate monohydrate, cystine and hydroxyproline, cystine and histidine, leucine and arginine, leucine and lysine hydrochloride, leucine and histidine, leucine and cystine, isoleucine and arginine, isoleucine and lysine hydrochloride, isoleucine and histidine, isoleucine and cystine, valine and arginine, valine and lysine hydrochloride, valine and histidine, valine and cystine, methionine and arginine, and methionine and lysine hydrochloride.

6. 6. The amino acid mixture according to claim 1, wherein the mixture ratio of amino acid 1 to amino acid 2 in the amino acid mixture having a co-amorphous structure is 0.1 to 10 in terms of molar ratio.

7. 7. The amino acid mixture according to claim 6, wherein the mixing ratio of amino acid 1 to amino acid 2 is 6:4 to 4:6 in terms of molar ratio.

8. A beverage comprising the amino acid mixture according to any one of claims 1 to 7.

9. A pharmaceutical comprising the amino acid mixture according to any one of claims 1 to 7.

10. A cosmetic product comprising the amino acid mixture according to any one of claims 1 to 7.

11. 8. The method for producing an amino acid mixture according to any one of claims 1 to 7, characterized in that at least two of the amino acids are charged into a ball mill in a molar ratio of 1:0.1 to 10, a grinding aid is added in an amount of 0.1 to 5% by weight of the total amount of all the amino acids, and the ball mill is operated at a rotation speed of 200 to 1200 rpm for 15 minutes to 12 hours.

12. The method for producing an amino acid mixture according to claim 11, characterized in that the pot of the ball mill is cooled to 5 to 15°C during operation of the ball mill.

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