Composition forming co-amorphous structure of amino acid or salt thereof and saccharide, and production method thereof

Abstract

To provide an amid acid-containing composition, etc. improved in water solubility.SOLUTION: A composition includes: (A) at least one kind of amino acid selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, or salt thereof; and (B) at least one kind of saccharide selected from the group consisting of sucrose and glucose, where at least a part of the (A) and at least a part of the (B) form a co-amorphous structure.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition in which an amino acid or a salt thereof and a sugar form a co-amorphous structure, and a method for producing the same.The present invention also relates to a method for improving the water solubility of an amino acid or a salt thereof. [Background technology]

[0002] Amino acids have many excellent functions such as nutritional function, physiological function, taste function, etc., and therefore are used in various fields such as food, medicine, feed, cosmetics, etc. Various studies have been conducted with the aim of improving the usability of such amino acids.

[0003] For example, focusing on the fact that the solubility of amino acids that normally exist as crystals can be improved by making them amorphous, it has been proposed to combine amino acids with organic acids to form co-amorphous structures (Patent Document 1) and to combine different types of amino acids to form co-amorphous structures (Patent Document 2).

[0004] On the other hand, in order to produce a solid dispersion in which a poorly water-soluble substance is stably dispersed at the molecular level in a solid matrix of a hydrophilic substance, it has been proposed to mix an amorphous hydrophilic substance produced using a hydrophilic substance selected from the group consisting of sugars, sugar alcohols, and amino acids with an organic solvent in which a poorly water-soluble substance has been dispersed, and then dry the mixture (Patent Document 3). It has also been proposed to use a spray-dried powder containing a predetermined amount of an active ingredient, leucine, and sugar in an inhalation formulation (Patent Document 4). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2021 / 187472 [Patent Document 2] International Publication No. 2020 / 262455 [Patent Document 3] JP 2015-193613 A [Patent Document 4] International Publication No. 2014 / 167023 Summary of the Invention [Problem to be solved by the invention]

[0006] The technology disclosed in the above-mentioned Patent Document 1 is a highly excellent technology for improving the solubility of amino acids, etc., but the co-amorphous structure of an amino acid and an organic acid has an acidic pH when dissolved in water, etc., and also has a strong sour taste, so there are cases where application to foods (e.g., products with a near-neutral pH) etc. is limited.

[0007] The present invention has been made in consideration of the above-mentioned circumstances, and the problem to be solved by the present invention is to provide a new method for improving the water solubility of an amino acid (preferably, a method for improving the water solubility of an amino acid while minimizing the effect on the pH and taste upon dissolution), and to provide a new amino acid-containing composition with improved water solubility and a method for producing the same (preferably, an amino acid-containing composition with improved water solubility while minimizing the effect on the pH and taste upon dissolution and a method for producing the same). [Means for solving the problem]

[0008] The present inventors have conducted intensive research to solve the above-mentioned problems, and have surprisingly found that a specific amino acid and a specific sugar can form a co-amorphous structure by crushing and mixing the specific amino acid with a specific sugar. They have also found that a composition in which a specific amino acid and a specific sugar form a co-amorphous structure can have improved water solubility. Based on these findings, the present inventors have conducted further research and have completed the present invention. That is, the present invention is as follows.

[0009] [1] (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, and (B) containing at least one sugar selected from the group consisting of sucrose and glucose; A composition, wherein at least a portion of (A) and at least a portion of (B) form a co-amorphous structure. [2] (i) The (A) contains at least leucine or a salt thereof, and the (B) contains at least sucrose; or (ii) The (A) contains at least valine or a salt thereof, and the (B) contains at least sucrose; (iii) The (A) contains at least isoleucine or a salt thereof, and the (B) contains at least sucrose; or (iv) The (A) contains at least cystine or a salt thereof, and the (B) contains at least sucrose; (v) containing at least tyrosine or a salt thereof as (A) and at least sucrose as (B); or (vi) The (A) contains at least glutamic acid or a salt thereof, and the (B) contains at least sucrose; (vii) The (A) contains at least arginine or a salt thereof, and the (B) contains at least sucrose, or (viii) The composition according to [1], comprising at least leucine or a salt thereof as (A) and at least glucose as (B). [3] The composition according to [1] or [2], wherein the molar ratio of (A) and (B) contained in the composition is A:B=1:0.1-10. [4] The composition according to any one of [1] to [3], wherein the content of (A) in the composition is 0.1 to 85% by weight based on the weight of the composition. [5] The composition according to any one of [1] to [4], wherein the content of (B) in the composition is 0.1 to 85% by weight based on the weight of the composition. [6] The composition according to any one of [1] to [5], which is a food composition, a pharmaceutical composition, a feed composition or a cosmetic composition. [7] A method for producing a food, a medicine, an animal feed, or a cosmetic product, comprising using the composition according to any one of [1] to [5]. [8] A food, medicine, feed, or cosmetic product comprising the composition according to any one of [1] to [5]. [9] A method comprising crushing and mixing (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, and (B) at least one sugar selected from the group consisting of sucrose and glucose, A method for producing a composition containing the (A) and the (B), in which at least a portion of the (A) and at least a portion of the (B) form a co-amorphous structure.

[10] The method according to [9], wherein the grinding and mixing of (A) and (B) is carried out using a ball mill.

[11] The method according to

[10] , wherein the rotation speed of a ball mill when grinding and mixing (A) and (B) is 300 to 2000 rpm.

[12] The method according to

[10] , wherein the rotation speed of a ball mill when (A) is pulverized and mixed with (B) is 500 to 1500 rpm.

[13] The method according to

[10] , wherein the rotation speed of a ball mill when (A) is pulverized and mixed with (B) is 800 to 1200 rpm.

[14] The method according to any one of [9] to

[13] , wherein the time for grinding and mixing (A) and (B) is 0.1 to 12 hours.

[15] The method according to any one of [9] to

[13] , wherein the time for grinding and mixing (A) with (B) is 0.5 to 5 hours.

[16] The method according to any one of [9] to

[13] , wherein the time for grinding and mixing (A) with (B) is 1 to 3 hours.

[17] (i) At least leucine or a salt thereof is used as the (A), and at least sucrose is used as the (B); (ii) at least valine or a salt thereof is used as (A) and at least sucrose is used as (B); (iii) at least isoleucine or a salt thereof is used as the (A) and at least sucrose is used as the (B); (iv) at least cystine or a salt thereof is used as (A) and at least sucrose is used as (B); (v) at least tyrosine or a salt thereof is used as the (A) and at least sucrose is used as the (B); (vi) at least glutamic acid or a salt thereof is used as the (A) and at least sucrose is used as the (B); (vii) at least arginine or a salt thereof is used as (A) and at least sucrose is used as (B), or (viii) The method according to any one of [9] to

[16] , wherein at least leucine or a salt thereof is used as (A), and at least glucose is used as (B).

[18] The method according to any one of [9] to

[17] , wherein the molar ratio of (A) and (B) to be ground and mixed is A:B=1:0.1-10.

[19] The method according to any one of [9] to

[18] , wherein the content of (A) in the composition is 0.1 to 85% by weight relative to the composition.

[20] The method according to any one of [9] to

[19] , wherein the content of (B) in the composition is 0.1 to 85% by weight relative to the composition.

[21] The method according to any one of [9] to

[20] , wherein the composition is a food composition, a pharmaceutical composition, a feed composition, or a cosmetic composition.

[22] A method for producing a food, a medicine, an animal feed, or a cosmetic product, comprising using a composition obtained by the method according to any one of [9] to

[21] .

[23] A method for improving the water solubility of (A), comprising grinding and mixing (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, together with (B) at least one sugar selected from the group consisting of sucrose and glucose, to form a co-amorphous structure between at least a portion of (A) and at least a portion of (B).

[24] The method according to

[23] , wherein the grinding and mixing of (A) and (B) is carried out using a ball mill.

[25] The method according to

[24] , wherein the rotation speed of a ball mill when (A) is pulverized and mixed with (B) is 300 to 2000 rpm.

[26] The method according to

[24] , wherein the rotation speed of a ball mill when (A) is pulverized and mixed with (B) is 500 to 1500 rpm.

[27] The method according to

[24] , wherein the rotation speed of a ball mill when (A) is pulverized and mixed with (B) is 800 to 1200 rpm.

[28] The method according to any one of

[23] to

[27] , wherein the time for grinding and mixing (A) with (B) is 0.1 to 12 hours.

[29] The method according to any one of

[23] to

[27] , wherein the time for grinding and mixing (A) with (B) is 0.5 to 5 hours.

[30] The method according to any one of

[23] to

[27] , wherein the time for grinding and mixing (A) with (B) is 1 to 3 hours.

[31] (i) At least leucine or a salt thereof is used as the (A), and at least sucrose is used as the (B); (ii) at least valine or a salt thereof is used as (A) and at least sucrose is used as (B); (iii) at least isoleucine or a salt thereof is used as the (A) and at least sucrose is used as the (B); (iv) at least cystine or a salt thereof is used as (A) and at least sucrose is used as (B); (v) at least tyrosine or a salt thereof is used as the (A) and at least sucrose is used as the (B); (vi) at least glutamic acid or a salt thereof is used as the (A) and at least sucrose is used as the (B); (vii) at least arginine or a salt thereof is used as (A) and at least sucrose is used as (B), or (viii) The method according to any one of

[23] to

[30] , wherein at least leucine or a salt thereof is used as (A), and at least glucose is used as (B).

[32] The method according to any one of

[23] to

[31] , wherein the molar ratio of (A) and (B) to be ground and mixed is A:B=1:0.1 to 10.

[33] The method according to any one of

[23] to

[32] , wherein the content of (A) in the composition is 0.1 to 85% by weight relative to the composition.

[34] The method according to any one of

[23] to

[33] , wherein the content of (B) in the composition is 0.1 to 85% by weight relative to the composition.

[35] The method according to any one of

[23] to

[34] , wherein the improvement in the water solubility of (A) is an improvement in the water dissolution rate and / or the water dissolution amount of (A). Effect of the Invention

[0010] According to the present invention, there is provided a method for improving the water solubility of a specific amino acid or a salt thereof. Since the method of the present invention does not require the use of an organic acid, the water solubility of the specific amino acid or a salt thereof can be improved while suppressing the effect on the pH and taste during dissolution. The present invention also provides a composition containing a specific amino acid or a salt thereof with improved water solubility, and a method for producing the same. The composition of the present invention does not necessarily contain an organic acid, and can suppress the effect on pH and taste when dissolved, so there is no restriction on its use in foods, etc. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows PXRD patterns of Leu-Suc[GM1] ("GM(2g,1h)"), Leu-Suc[GM2] ("GM(10g,12h)"), Leu-Suc[PM1] ("PM"), sucrose ("Suc"), and L-leucine ("Leu") obtained in Test Example 1. [Diagram 2] FIG. 1 shows PXRD patterns of Leu-Suc[GM3] ("GM(2g,1h)"), Leu-Suc[GM4] ("GM(10g,12h)"), Leu-Suc[PM2] ("PM"), sucrose ("Suc"), and L-leucine ("Leu") obtained in Test Example 1. [Diagram 3] FIG. 1 shows PXRD patterns of Leu-Suc[GM5] ("GM(2g,1h)"), Leu-Suc[GM6] ("GM(10g,12h)"), Leu-Suc[PM3] ("PM"), sucrose ("Suc"), and L-leucine ("Leu") obtained in Test Example 1. [Figure 4] FIG. 1 shows PXRD patterns of Leu-Suc[GM7] ("GM(2g,1h)"), Leu-Suc[GM8] ("GM(10g,12h)"), Leu-Suc[PM4] ("PM"), sucrose ("Suc"), and L-leucine ("Leu") obtained in Test Example 1. [Diagram 5] PXRD patterns of Gly-Suc[GM] ("GM" in the figure), Gly-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and glycine ("Gly" in the figure) obtained in Test Example 2. [Figure 6]PXRD patterns of Val-Suc[GM] ("GM" in the figure), Val-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-valine ("Val" in the figure) obtained in Test Example 2. [Figure 7] PXRD patterns of Ile-Suc[GM] ("GM" in the figure), Ile-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-isoleucine ("Ile" in the figure) obtained in Test Example 2. [Figure 8] PXRD patterns of Cys2-Suc[GM] ("GM" in the figure), Cys2-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and cystine ("Cys2" in the figure) obtained in Test Example 2. [Figure 9] PXRD patterns of Tyr-Suc[GM] ("GM" in the figure), Tyr-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-tyrosine ("Tyr" in the figure) obtained in Test Example 2. [Figure 10] FIG. 1 shows the PXRD patterns of Glu-Suc[GM] ("GM" in the figure), Glu-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-glutamic acid ("Glu" in the figure) obtained in Test Example 2. [Figure 11] PXRD patterns of Arg-Suc[GM] ("GM" in the figure), Arg-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-arginine ("Arg" in the figure) obtained in Test Example 2. [Figure 12] PXRD patterns of Leu-Glc[GM] ("GM" in the figure), Leu-Glc[PM] ("PM" in the figure), glucose ("Glc" in the figure), and L-leucine ("Leu" in the figure) obtained in Test Example 2. [Figure 13] PXRD patterns of Leu-Tre[GM] ("GM" in the figure), Leu-Tre[PM] ("PM" in the figure), trehalose ("Tre" in the figure), and L-leucine ("Leu" in the figure) obtained in Test Example 2. [Figure 14]1 shows DSC patterns of Gly-Suc[GM] ("GM" in the figure), Gly-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and glycine ("Gly" in the figure) obtained in Test Example 2. "Endo." on the vertical axis indicates endothermic reaction, and "Exo." indicates exothermic reaction. [Figure 15] This shows DSC patterns of Tyr-Suc[GM] ("GM" in the figure), Tyr-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-tyrosine ("Tyr" in the figure) obtained in Test Example 2. "Endo." on the vertical axis means endothermic reaction, and "Exo." means exothermic reaction. [Figure 16] 1 shows DSC patterns of Glu-Suc[GM] ("GM" in the figure), Glu-Suc[PM] ("PM" in the figure), sucrose ("Suc" in the figure), and L-glutamic acid ("Glu" in the figure) obtained in Test Example 2. "Endo." on the vertical axis indicates endothermic reaction, and "Exo." indicates exothermic reaction. [Figure 17] 1 is a graph showing the volume-based particle size distribution of Leu-Suc[GM1], Leu-Suc[GM7], Leu-Suc[PM1], and Leu-Suc[PM4] ("Leu[PM1,PM4]" in the figure) used in Test Example 3. The vertical axis of the graph shows the logarithm of the frequency distribution, and the horizontal axis shows the particle size. [Figure 18] 1 is a graph showing the results of a test to confirm the water dissolution rate of Leu-Suc[GM1] and Leu-Suc[PM1] in Test Example 3. [Figure 19] 1 is a graph showing the results of a test to confirm the water dissolution rate of Leu-Suc[GM7] and Leu-Suc[PM4] in Test Example 3. [Figure 20] 1 is a graph showing the results of a test to confirm the water solubility of Cys2-Suc[GM] and Cys2-Suc[PM] in Test Example 3. [Figure 21] 1 is a graph showing the results of a test to confirm the water solubility of Tyr-Suc[GM] and Tyr-Suc[PM] in Test Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The composition of the present invention contains (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, and (B) at least one sugar selected from the group consisting of sucrose and glucose. In this specification, for convenience of explanation, "at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine" and "at least one sugar selected from the group consisting of sucrose and glucose" may be referred to simply as "(A)" and "(B)", respectively.

[0013] The amino acids that may be contained as (A) in the composition of the present invention (i.e., leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, arginine) may be in any of the L-, D-, and DL-forms, but are preferably in the L- or DL-form, and more preferably in the L-form.

[0014] The amino acids (i.e., leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine) used in the present invention are preferably in the free form or a salt thereof. Here, the term "free form" refers to an amino acid that does not bind with other amino acids to form proteins, peptides, etc., and exists in a free state.

[0015] The type of amino acid salt that can be contained as (A) in the composition of the present invention is not particularly limited as long as it is acceptable as a food, medicine, etc., and examples thereof include salts with inorganic acids (e.g., hydrogen chloride, hydrogen bromide, hydroiodic acid, sulfuric acid, phosphoric acid, etc.); salts with organic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, fumaric acid, monomethylsulfuric acid, etc.); salts with inorganic bases (e.g., sodium, potassium, lithium, calcium, ammonia, etc.); salts with organic bases (e.g., ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, triethanolamine, etc.). The amino acid salt may be a hydrate (hydrated salt), and examples of the hydrate include monohydrate to hexahydrate.

[0016] The composition of the present invention may contain as (A) only one of the various amino acids and salts thereof described above, or may contain two or more of the various amino acids and salts thereof described above.

[0017] The composition of the present invention may contain only one of sucrose and glucose as (B), or may contain both sucrose and glucose. Glucose may be either L-form or D-form, but is preferably D-form (D-glucose).

[0018] The combination of the type of (A) (i.e., at least one amino acid selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine) and the type of (B) (i.e., at least one sugar selected from the group consisting of sucrose and glucose) that may be contained in the composition of the present invention is not particularly limited, and for example, the composition of the present invention may contain a combination of (A) and (B) as shown in the following (i) to (xiii). (i) (A) contains at least leucine or a salt thereof, and (B) contains at least sucrose (preferably, (A) is leucine or a salt thereof, and (B) is sucrose). (ii) (A) contains at least valine or a salt thereof, and (B) contains at least sucrose (preferably, (A) is valine or a salt thereof, and (B) is sucrose). (iii) (A) contains at least isoleucine or a salt thereof, and (B) contains at least sucrose (preferably, (A) is isoleucine or a salt thereof, and (B) is sucrose). (iv) (A) contains at least cystine or a salt thereof, and (B) contains at least sucrose (preferably, (A) is cystine or a salt thereof, and (B) is sucrose). (v) Contains at least tyrosine or a salt thereof as (A) and at least sucrose as (B) (preferably, (A) is tyrosine or a salt thereof, and (B) is sucrose). (vi) Contains at least glutamic acid or a salt thereof as (A) and at least sucrose as (B) (preferably, (A) is glutamic acid or a salt thereof and (B) is sucrose). (vii) (A) contains at least arginine or a salt thereof, and (B) contains at least sucrose (preferably, (A) is arginine or a salt thereof, and (B) is sucrose). (viii) (A) contains at least leucine or a salt thereof, and (B) contains at least glucose (preferably, (A) is leucine or a salt thereof, and (B) is glucose). (ix) (A) contains at least valine or a salt thereof, and (B) contains at least glucose (preferably, (A) is valine or a salt thereof, and (B) is glucose). (x) (A) contains at least isoleucine or a salt thereof, and (B) contains at least glucose (preferably, (A) is isoleucine or a salt thereof, and (B) is glucose). (xi) (A) contains at least cystine or a salt thereof, and (B) contains at least glucose (preferably, (A) is cystine or a salt thereof, and (B) is glucose). (xii) (A) contains at least tyrosine or a salt thereof, and (B) contains at least glucose (preferably, (A) is tyrosine or a salt thereof, and (B) is glucose). (xiii) (A) contains at least glutamic acid or a salt thereof, and (B) contains at least glucose (preferably, (A) is glutamic acid or a salt thereof, and (B) is glucose). In particular, the composition of the present invention preferably contains (A) and (B) as in any one of the above (i) to (viii).

[0019] One of the characteristics of the composition of the present invention is that at least a part of (A) and at least a part of (B) form a co-amorphous structure. In the present invention, the term "co-amorphous structure" refers to a stable amorphous structure formed by two or more substances. Here, the term "amorphous structure" refers to a structure in which the atoms or molecules of a substance are irregularly arranged without the long-range order usually observed in a crystal.

[0020] The presence or absence of the formation of the co-amorphous structure can be confirmed by a method known per se or a method equivalent thereto, but in the present invention, the presence or absence of the formation of the co-amorphous structure is preferably confirmed by powder X-ray diffraction (PXRD). In detail, the X-ray diffraction pattern (also referred to as "PXRD pattern" in this specification) is obtained by performing analysis by powder X-ray diffraction using Cu-Kα radiation as a radiation source, and the presence or absence of the formation of the co-amorphous structure can be determined by confirming the detection of a halo peak (broad peak) and a crystalline peak in the region of the diffraction angle (2θ) of 4 to 40° in the PXRD pattern. When a crystalline peak is not detected and a halo peak is detected, it is determined that a co-amorphous structure is formed, and conversely, when a halo peak is not detected and a crystalline peak is detected, it is determined that a co-amorphous structure is not formed. When both halo peaks and crystalline peaks are detected and the presence or absence of a co-amorphous structure cannot be clearly determined by the analysis by powder X-ray diffraction, the presence or absence of a co-amorphous structure can be determined by using differential scanning calorimetry (DSC) in combination. When both a baseline shift due to glass transition and an exothermic peak associated with crystallization are detected in the pattern obtained by the analysis by differential scanning calorimetry (also referred to as "DSC pattern" in this specification), it is determined that a co-amorphous structure is formed. When at least one of the baseline shift and the exothermic peak is not detected, it is determined that a co-amorphous structure is not formed. Note that when the formation of a co-amorphous structure can be clearly determined by the analysis by powder X-ray diffraction, it may be determined that a co-amorphous structure is formed even if at least one of the baseline shift and the exothermic peak is not detected in the DSC pattern.

[0021] In the composition of the present invention, the co-amorphous structure may be formed by at least a part of (A) and at least a part of (B), but the proportion of (A) contained in the composition of the present invention that forms the co-amorphous structure is preferably 50% or more, more preferably 70% or more, and particularly preferably 90% or more. This proportion can be calculated by a multiple peak separation method of powder X-ray diffraction measurement. In addition, the proportion of (B) contained in the composition of the present invention that forms the co-amorphous structure is preferably 50% or more, more preferably 70% or more, and particularly preferably 90% or more. This proportion can also be calculated by a multiple peak separation method of powder X-ray diffraction measurement.

[0022] The molar ratio of (A) and (B) contained in the composition of the present invention is preferably A:B=1:0.1-10, more preferably A:B=1:0.2-5, even more preferably A:B=1:0.3-3, and particularly preferably A:B=1:0.5-1.5.

[0023] The content of (A) in the composition of the present invention is not particularly limited, but is usually 0.1 to 85% by weight, preferably 1 to 80% by weight, and more preferably 10 to 75% by weight, based on the composition of the present invention.

[0024] The content of (B) in the composition of the present invention is not particularly limited, but is usually 0.1 to 85% by weight, preferably 1 to 80% by weight, and more preferably 10 to 75% by weight, based on the composition of the present invention.

[0025] The total content of (A) and (B) in the composition of the present invention is not particularly limited, but is usually 0.1 to 100% by weight, preferably 1 to 99% by weight, and more preferably 10 to 90% by weight, based on the composition of the present invention.

[0026] The composition of the present invention can be provided as a raw material for, for example, food, medicine, feed, cosmetics, etc. That is, the composition of the present invention may be, in one embodiment, a food composition, a pharmaceutical composition, a feed composition, a cosmetic composition, etc. In the present invention, the term "food" is a concept that broadly includes anything that can be orally ingested (excluding medicines), and includes beverages, seasonings, food additives, health foods, supplements, etc. In addition, "food composition", "pharmaceutical composition", "feed composition", and "cosmetic composition" refer to compositions that are used as raw materials for food, medicine, feed, and cosmetics, respectively.

[0027] In one embodiment, the composition of the present invention may be a raw material for a product that can be orally ingested (eg, a food composition, an oral pharmaceutical composition, a feed composition, etc.).

[0028] The form of the composition of the present invention is not particularly limited, and examples thereof include solid forms (e.g., powder, granules, tablets, capsules, etc.), semi-solid forms (e.g., gels, jelly, creams, etc.), liquid forms (e.g., suspensions, emulsions, etc.), and combinations of these forms.

[0029] The composition of the present invention may consist of only (A) and (B), but may further contain substances other than (A) and (B) in addition to (A) and (B). The substances other than (A) and (B) that may be contained in the composition of the present invention are not particularly limited as long as they do not impair the object of the present invention, and may be appropriately selected depending on the form and usage mode of the composition of the present invention.When the composition of the present invention is, as one embodiment, a food composition, examples of substances other than (A) and (B) that may be contained in the composition of the present invention include binders such as tragacanth, gum arabic, corn starch, gelatin, and polymeric polyvinylpyrrolidone; excipients such as cellulose and its derivatives (e.g., microcrystalline cellulose, crystalline cellulose, hydroxypropyl cellulose, etc.); leavening agents such as corn starch, pregelatinized starch, alginic acid, and dextrin; lubricants such as magnesium stearate; flow improvers such as fine silicon dioxide and methyl cellulose; lubricants such as glycerin fatty acid esters, talc, and polyethylene glycol 6000; thickeners such as sodium carboxymethylcellulose, carboxyvinyl polymers, xanthan gum, and gelatin; sweeteners such as various sugars other than (B), aspartame, acesulfame potassium, stevia, saccharin, and licorice; flavorings such as peppermint flavor, vanilla flavor, cherry flavor, and orange flavor; monoglycerides, polyglycerins, and the like. Emulsifiers such as fatty acid esters, sucrose fatty acid esters, lecithin (e.g., soybean lecithin, etc.), polyoxyethylene hydrogenated castor oil, polyoxyethylene monostearate ester, and beeswax; pH adjusters such as citric acid, sodium citrate, acetic acid, sodium acetate, and sodium hydroxide; antioxidants such as erythorbic acid, butylated hydroxyanisole, and propyl gallate; sodium benzoate, sodium edetate, sorbic acid, sodium sorbate, methyl parahydroxybenzoate, and butyl parahydroxybenzoate. Examples of the additives include, but are not limited to, preservatives such as ferric iron oxide, iron oxide black, carmine, food blue No. 1, food yellow No. 4, and food red No. 2, colorants such as red iron oxide, yellow iron oxide, black iron oxide, carmine, food blue No. 1, food yellow No. 4, and food red No. 2, fats and oils such as safflower oil, antioxidants such as vitamin C, vitamin A, vitamin E, various polyphenols, and hydroxythiosol, coating agents such as shellac, hydroxypropylmethylcellulose phthalate, and polyacetin, preservatives such as methylparaben and propylparaben, various vitamins, various amino acids other than (A), water, and organic acids or salts thereof. In addition, when the composition of the present invention is a food composition as one embodiment, the composition of the present invention may contain food ingredients according to the type of food, etc.

[0030] When the composition of the present invention contains, in addition to (A) and (B), a substance other than (A) and (B), at least a portion of the substance may form a co-amorphous structure with at least a portion of (A) and at least a portion of (B).

[0031] The above-mentioned co-amorphous structure of the composition of the present invention can be formed by grinding and mixing (A) and (B) together. Therefore, the method for producing the composition of the present invention preferably includes grinding and mixing (A) and (B).

[0032] In the method for producing the composition of the present invention, the grinding and mixing of (A) and (B) may be carried out using a ball mill. Examples of ball mills that may be used include "Retsch (registered trademark) Emax" from Verder Scientific, "Planetary Ball Mill" from Kurimoto Iron Works, Ltd., "Attritor" from Nippon Coke and Engineering Co., Ltd., and "Simoloyer (registered trademark)" from Zoz GmbH.

[0033] The capacity of the grinding container (also called mill pot or grinding jar) of the ball mill is not particularly limited, but is usually 10 to 500 mL, preferably 50 to 200 mL, and more preferably 100 to 150 mL.

[0034] The diameter of the balls (also called grinding balls) of the ball mill is not particularly limited, but is usually 0.1 mm to 15 mm, preferably 1 to 12 mm, and more preferably 5 to 10 mm.

[0035] The number of balls to be placed in the grinding vessel of the ball mill is not particularly limited and may be appropriately adjusted depending on the capacity of the grinding vessel, etc., but is usually 10 to 100, preferably 20 to 80, and more preferably 40 to 60.

[0036] The total amount of (A) and (B) (total charge amount) to be placed in the grinding container of the ball mill may be adjusted appropriately depending on the capacity of the grinding container, etc., but is usually 0.5 to 10 g, preferably 1 to 5 g, and more preferably 1.5 to 2.5 g.

[0037] The molar ratio of (A) and (B) to be placed in the grinding vessel of the ball mill (i.e., to be ground and mixed) is preferably A:B=1:0.1-10, more preferably A:B=1:0.2-5, even more preferably A:B=1:0.3-3, and particularly preferably A:B=1:0.5-1.5.

[0038] The manufacturing method of (A) and (B) to be put into the grinding container of the ball mill is not particularly limited, and each of them may be manufactured by a method known per se or a method similar thereto. Alternatively, each of them may be a commercially available product. The form of (A) and (B) to be put into the grinding container of the ball mill is not particularly limited, but is preferably powder or granular. (A) and (B) to be put into the grinding container of the ball mill may be crystalline or amorphous.

[0039] The combination of the type of (A) and the type of (B) to be placed in the grinding vessel of the ball mill (i.e., to be ground and mixed) is the same as the combination of the type of (A) and the type of (B) that can be contained in the composition of the present invention described above, and the preferred combinations are also the same.

[0040] In addition to (A) and (B), a grinding aid (e.g., ethanol, water, isopropanol, ethyl acetate, acetone, petroleum ether, heptane, etc.) may be further placed in the grinding vessel of the ball mill. By adding the grinding aid, it is possible to prevent the solidification of (A) and (B). The amount of the grinding aid to be placed in the grinding vessel of the ball mill is usually 0.1 to 10% (v / w), preferably 1 to 5% (v / w), based on the total amount of (A) and (B) placed in the grinding vessel of the ball mill.

[0041] The rotation speed of the ball mill when (A) and (B) are pulverized and mixed is preferably 300 to 2000 rpm, more preferably 500 to 1500 rpm, and particularly preferably 800 to 1200 rpm.

[0042] The time for grinding and mixing (A) and (B) (i.e., the operation time of the ball mill) is usually 0.1 to 12 hours, preferably 0.5 to 5 hours, and more preferably 1 to 3 hours. Note that the ball mill is preferably operated while being appropriately cooled (e.g., to 15°C or less), so that it can be operated continuously without a pause for cooling.

[0043] The powder obtained by grinding and mixing (A) and (B) using a ball mill under the above-mentioned conditions may be used as the composition of the present invention as it is, or may be subjected to further treatment or manufacturing steps.

[0044] The method for producing the composition of the present invention may further include other production steps in addition to grinding and mixing (A) and (B). The production steps other than grinding and mixing (A) and (B) are not particularly limited as long as they do not impair the object of the present invention, and may be appropriately carried out depending on the type of the composition of the present invention, raw materials, etc.

[0045] The composition of the present invention preferably has improved water solubility (e.g., water dissolution rate, water dissolution amount, etc.). The water solubility (e.g., water dissolution rate, water dissolution amount, etc.) of the composition of the present invention can be confirmed by a method known per se or a method equivalent thereto. For example, the water dissolution rate and water dissolution amount of the composition of the present invention can be confirmed by a water dissolution rate confirmation test and a water dissolution amount confirmation test, respectively, in the Examples (Test Example 3) described later.

[0046] The composition of the present invention may have improved water solubility (e.g., water dissolution rate, etc.), and therefore, by using the composition of the present invention in the production of foods and the like, the texture (e.g., melt-in-the-mouth texture, etc.) of the foods and the like may be improved. Furthermore, since the composition of the present invention may have improved water solubility (e.g., water dissolution rate, etc.), the productivity of the product may be improved by utilizing the composition of the present invention in product production (e.g., production of foods, medicines, feeds, cosmetics, etc.). Furthermore, the composition of the present invention may have improved water solubility (e.g., water solubility amount, etc.), and therefore, by utilizing the composition of the present invention in the production of products, the amount of water used may be reduced.

[0047] In one embodiment, the composition of the present invention can be used as a raw material for food, medicine, feed, cosmetics, etc., and the present invention also provides a method for producing food, medicine, feed, or cosmetics (sometimes referred to as the "production method of the present invention" in this specification) that includes using the composition of the present invention. The production method of the present invention is not particularly limited except that the composition of the present invention is used as a raw material, and may further include normal production steps and treatment steps for food, medicine, feed, or cosmetics as necessary, as long as the object of the present invention is not impaired. For example, the production method of the present invention may include a step of dissolving the composition of the present invention in water, etc.

[0048] (A) (i.e., at least one amino acid or salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine) and (B) (i.e., at least one sugar selected from the group consisting of sucrose and glucose) contained in a food, medicine, feed, or cosmetic product obtained by the production method of the present invention may form a co-amorphous structure, or may not form a co-amorphous structure. For example, (A) and (B) contained in a beverage obtained by the production method of the present invention may be dissolved in the beverage and not form a co-amorphous structure.

[0049] The types of food, medicine, feed, and cosmetics obtained by the manufacturing method of the present invention are not particularly limited. Specific examples of foods obtained by the manufacturing method of the present invention include, but are not limited to, processed foods (e.g., processed agricultural foods, processed livestock foods, processed marine foods, instant foods, seasonings, confectioneries, etc.), beverages (including powdered beverages), etc. Foods obtained by the manufacturing method of the present invention may be provided as health functional foods (specified health foods, functional foods, nutritional functional foods), special purpose foods, nutritional supplements, supplements, etc. Specific examples of medicines obtained by the manufacturing method of the present invention include, but are not limited to, oral medicines (e.g., tablets, granules, powders, capsules, elixirs, syrups, microcapsules, drinks, emulsions, suspensions, etc.), parenteral medicines (e.g., ointments, creams, gels, liquids, lotions, packs, bath additives, injections, etc.). Specific examples of cosmetics obtainable by the production method of the present invention include, but are not limited to, hair cosmetics (e.g., hair styling products, hair care products, hair washes, hair rinses, etc.), skin cosmetics (e.g., skin lotions, skin care fluids, sunscreens, cleansers, etc.), finishing cosmetics (e.g., foundations, lipsticks, eye make-up, etc.), perfumes, colognes, medicated cosmetics, etc.

[0050] The present invention also provides a food comprising the composition of the present invention, a medicine comprising the composition of the present invention, a feed comprising the composition of the present invention, and a cosmetic comprising the composition of the present invention (collectively referred to herein as "food, etc. of the present invention"). The food, etc. of the present invention is not particularly limited except that it comprises the composition of the present invention. The food, etc. of the present invention may further comprise other raw materials, etc. in addition to the composition of the present invention, or may consist only of the composition of the present invention. The type of food, etc. of the present invention is not particularly limited, and may be the same as the food, etc. obtained by the above-mentioned production method of the present invention. The production method of the food, etc. of the present invention is also not particularly limited, and may be produced by a method known per se or a method equivalent thereto.

[0051] The present invention also provides a method for improving the water solubility of (A) (i.e., at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine) (sometimes referred to in this specification as the "method of the present invention"). The method of the present invention comprises grinding and mixing (A) with (B) (i.e., at least one sugar selected from the group consisting of sucrose and glucose) to form a co-amorphous structure between at least a portion of (A) and at least a portion of (B).

[0052] In the method of the present invention, the grinding and mixing of (A) and (B) may be carried out in the same manner as the grinding and mixing of (A) and (B) in the above-mentioned method for producing the composition of the present invention, and the preferred embodiments are also the same.

[0053] A composition obtained by grinding and mixing (A) with (B) and forming a co-amorphous structure between at least a part of (A) and at least a part of (B) can have superior water solubility (e.g., water dissolution rate, water dissolution amount, etc.) compared to (A). Thus, according to the method of the present invention, the water solubility (e.g., water dissolution rate, water dissolution amount, etc.) of (A) can be improved.

[0054] The method of the present invention does not necessarily require the use of an organic acid, and therefore the water solubility of (A) can be improved while suppressing the effects on the pH and taste during dissolution. In addition, when an amino acid or a salt thereof is generally solubilized with an additive, the oral absorbability of the amino acid or a salt thereof may decrease. However, the method of the present invention can improve the aqueous solubility of (A) without decreasing the oral absorbability.

[0055] According to the method of the present invention, the water dissolution rate of (A) can be increased, and therefore, in one embodiment, the method of the present invention may be a method for increasing the water dissolution rate of (A). Furthermore, according to the method of the present invention, the water solubility of (A) can be increased, and therefore, in one embodiment, the method of the present invention may be a method for increasing the water solubility of (A). One embodiment of the method of the present invention may be a method for improving the water dissolution rate and water dissolution amount of (A).

[0056] The present invention will be described in more detail in the following examples, but the present invention is not limited to these examples in any way. EXAMPLES

[0057] The sources of the reagents used in the following Test Examples 1 to 3 are shown in Table 1. The amino acids and sugars shown in Table 1 are all in the form of crystalline powder.

[0058] [Table 1]

[0059] In the following Test Examples 1 to 3, a ball mill "Retsch (registered trademark) Emax" manufactured by Verder Scientific was used. The grinding container and balls were dried in a dryer at 105°C for 2 hours or more and allowed to cool in a desiccator before use.

[0060] In the following Test Examples 1 to 3, analysis by powder X-ray diffraction method (PXRD method) was carried out under the following conditions. [PXRD analysis conditions] Equipment: D2 PHASER (Bruker) ·Analysis method: Reflection method Output: 30kV, 10mA ·Radiation source: Cu-Kα radiation Diffraction angle (2θ): 4~40° Scan speed: 0.1° / sec

[0061] <Test Example 1> (Preparation of Ground Mixture 1 of L-Leucine and Sucrose (Leu-Suc[GM1])) 1 g (0.0076 mol) of L-leucine and 1 g (0.0029 mol) of sucrose were placed in a grinding container together with 50 balls, and then allowed to stand for 3 minutes or more in a glove box filled with nitrogen gas and adjusted to a humidity of 25% RH or less. Next, a grinding aid (absolute ethanol) was added to the grinding container, and grinding and mixing were performed using a ball mill under the following conditions. The ball mill was cooled by circulating cooling water during operation. [Ball mill grinding conditions] Grinding container: Zirconia, 125mL container Balls: Zirconia, 10mm diameter, 50 pieces Rotational speed: 1000 rpm Amount of ground powder: 2g (total amount of L-leucine and sucrose) Grinding time: 1 hour Grinding aid: absolute ethanol, added at 4% (v / w) based on grinding amount ·Cooling water: 8℃ The resulting ground mixture (hereinafter also referred to as "Leu-Suc[GM1]") was in the form of a powder, which was collected in a polyethylene bag in a glove box and stored in an aluminum pouch containing silica gel.

[0062] (Preparation of Ground Mixture 2 of L-Leucine and Sucrose (Leu-Suc[GM2])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM2]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose in the milling container were changed to 5 g (0.0381 mol) and 5 g (0.0146 mol), respectively (i.e., the milling amount in the ball mill milling conditions was 10 g), and the milling time in the ball mill milling conditions was changed to 12 hours. The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0063] (Preparation of physical mixture 1 of L-leucine and sucrose (Leu-Suc[PM1])) L-leucine and sucrose were mixed in the same molar ratio as Leu-Suc[GM1] and Leu-Suc[GM2] (L-leucine:sucrose = 1:0.38), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Leu-Suc[PM1]").

[0064] (Preparation of Ground Mixture 3 of L-Leucine and Sucrose (Leu-Suc[GM3])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM3]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose were changed to 1.2 g (0.0091 mol) and 0.8 g (0.0023 mol) in the milling container (i.e., the milling amount in the ball milling conditions was 2 g). The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0065] (Preparation of Ground Mixture 4 of L-Leucine and Sucrose (Leu-Suc[GM4])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM4]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose in the milling container were changed to 6 g (0.0457 mol) and 4 g (0.0117 mol), respectively (i.e., the milling amount in the ball mill milling conditions was 10 g), and the milling time in the ball mill milling conditions was changed to 12 hours. The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0066] (Preparation of physical mixture 2 of L-leucine and sucrose (Leu-Suc[PM2])) L-leucine and sucrose were mixed in the same molar ratio as Leu-Suc[GM3] and Leu-Suc[GM4] (L-leucine:sucrose = 1:0.26), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Leu-Suc[PM2]").

[0067] (Preparation of Ground Mixture 5 of L-Leucine and Sucrose (Leu-Suc[GM5])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM5]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose were changed to 1.4 g (0.0107 mol) and 0.6 g (0.0018 mol) in the milling container (i.e., the milling amount in the ball milling conditions was 2 g). The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0068] (Preparation of Ground Mixture 6 of L-Leucine and Sucrose (Leu-Suc[GM6])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM6]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose in the milling container were changed to 7 g (0.0534 mol) and 3 g (0.0088 mol), respectively (i.e., the milling amount in the ball mill milling conditions was 10 g), and the milling time in the ball mill milling conditions was changed to 12 hours. The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0069] (Preparation of physical mixture 3 of L-leucine and sucrose (Leu-Suc[PM3])) L-leucine and sucrose were mixed in the same molar ratio as Leu-Suc[GM5] and Leu-Suc[GM6] (L-leucine:sucrose = 1:0.16), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Leu-Suc[PM3]").

[0070] (Preparation of Ground Mixture 7 of L-Leucine and Sucrose (Leu-Suc[GM7])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM7]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose were changed to 0.55 g (0.0042 mol) and 1.45 g (0.0042 mol) in the milling container (i.e., the milling amount in the ball milling conditions was 2 g). The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0071] (Preparation of Ground Mixture 8 of L-Leucine and Sucrose (Leu-Suc[GM8])) A milled mixture (hereinafter also referred to as "Leu-Suc[GM8]") was prepared in the same manner as Leu-Suc[GM1], except that the amount of L-leucine and the amount of sucrose in the milling container were changed to 2.75 g (0.0210 mol) and 7.25 g (0.0212 mol), respectively (i.e., the milling amount in the ball mill milling conditions was 10 g), and the milling time in the ball mill milling conditions was changed to 12 hours. The prepared milled mixture was in powder form and was stored in the same manner as Leu-Suc[GM1].

[0072] (Preparation of physical mixture 4 of L-leucine and sucrose (Leu-Suc[PM4])) L-leucine and sucrose were mixed in the same molar ratio as Leu-Suc[GM7] and Leu-Suc[GM8] (L-leucine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Leu-Suc[PM4]").

[0073] (PXRD analysis) The ground mixtures (Leu-Suc[GM1], Leu-Suc[GM2], Leu-Suc[GM3], Leu-Suc[GM4], Leu-Suc[GM5], Leu-Suc[GM6], Leu-Suc[GM7] and Leu-Suc[GM8]) and physical mixtures (Leu-Suc[PM1], Leu-Suc[PM2], Leu-Suc[PM3] and Leu-Suc[PM4]) obtained above were analyzed by the PXRD method. In addition, as a control during the analysis, the amino acid (L-leucine) and sugar (sucrose) used as the raw material for the ground mixture were each analyzed by the PXRD method. The amino acid and sugar were each ground in an agate mortar for about 5 minutes and used in a homogeneous state. The obtained PXRD patterns are shown in Figures 1 to 4.

[0074] As shown in the PXRD patterns of Figures 1 to 4, no halo peak (broad peak) was detected in Leu-Suc[GM2], Leu-Suc[GM4], Leu-Suc[GM6] and Leu-Suc[GM8], but a crystalline peak was detected, whereas no crystalline peak was detected in Leu-Suc[GM1], Leu-Suc[GM3], Leu-Suc[GM5] and Leu-Suc[GM7], and a halo peak was detected. Therefore, it was confirmed that Leu-Suc[GM1], Leu-Suc[GM3], Leu-Suc[GM5] and Leu-Suc[GM7] all form a co-amorphous structure with L-leucine and sucrose. From these results, it was confirmed that L-leucine and sucrose form a co-amorphous structure by grinding and mixing under specific grinding conditions using a ball mill.

[0075] <Test Example 2> (Preparation of Ground Mixture of Glycine and Sucrose (Gly-Suc[GM])) 0.360g (0.00480mol) of glycine and 1.640g (0.00479mol) of sucrose were placed in a grinding container together with 50 balls, and then allowed to stand for 3 minutes or more in a glove box filled with nitrogen gas and adjusted to a humidity of 25% RH or less. Next, a grinding aid (absolute ethanol) was added to the grinding container, and grinding and mixing were performed using a ball mill under the following conditions. The ball mill was cooled by circulating cooling water during operation. [Ball mill grinding conditions] Grinding container: Zirconia, 125mL container Balls: Zirconia, 10mm diameter, 50 pieces Rotational speed: 1000 rpm Amount of ground powder: 2g (total amount of glycine and sucrose) Grinding time: 1 hour Grinding aid: absolute ethanol, added at 4% (v / w) based on grinding amount ·Cooling water: 8℃ The obtained ground mixture (hereinafter also referred to as "Gly-Suc[GM]") was in powder form, and was collected in a polyethylene bag in a glove box and stored in an aluminum pouch containing silica gel.

[0076] (Preparation of a physical mixture of glycine and sucrose (Gly-Suc[PM])) Glycine and sucrose were mixed in the same molar ratio as Gly-Suc[GM] (glycine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Gly-Suc[PM]").

[0077] (Preparation of Ground Mixture of L-Valine and Sucrose (Val-Suc[GM])) A milled mixture (hereinafter also referred to as "Val-Suc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.510 g (0.00435 mol) of L-valine and 1.490 g (0.00435 mol) of sucrose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0078] (Preparation of physical mixture of L-valine and sucrose (Val-Suc[PM])) L-valine and sucrose were mixed in the same molar ratio as Val-Suc[GM] (L-valine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Val-Suc[PM]").

[0079] (Preparation of Ground Mixture of L-Isoleucine and Sucrose (Ile-Suc[GM])) A milled mixture (hereinafter also referred to as "Ile-Suc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.550 g (0.00419 mol) of L-isoleucine and 1.450 g (0.00424 mol) of sucrose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0080] (Preparation of a physical mixture of L-isoleucine and sucrose (Ile-Suc[PM])) L-isoleucine and sucrose were mixed in the same molar ratio as Ile-Suc[GM] (L-isoleucine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Ile-Suc[PM]").

[0081] (Preparation of ground mixture of cystine and sucrose (Cys2-Suc[GM])) A milled mixture (hereinafter also referred to as "Cys2-Suc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.830 g (0.00345 mol) of cystine and 1.170 g (0.00342 mol) of sucrose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0082] (Preparation of a physical mixture of cystine and sucrose (Cys2-Suc[PM])) Cystine and sucrose were mixed in the same molar ratio as Cys2-Suc[GM] (cystine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Cys2-Suc[PM]").

[0083] (Preparation of Ground Mixture of L-Tyrosine and Sucrose (Tyr-Suc [GM])) A milled mixture (hereinafter also referred to as "Tyr-Suc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.690 g (0.00381 mol) of L-tyrosine and 1.310 g (0.00383 mol) of sucrose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0084] (Preparation of physical mixture of L-tyrosine and sucrose (Tyr-Suc[PM])) L-tyrosine and sucrose were mixed in the same molar ratio as Tyr-Suc[GM] (L-tyrosine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Tyr-Suc[PM]").

[0085] (Preparation of Ground Mixture of L-Glutamic Acid and Sucrose (Glu-Suc [GM])) A milled mixture (hereinafter also referred to as "Glu-Suc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.600 g (0.00408 mol) of L-glutamic acid and 1.400 g (0.00409 mol) of sucrose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0086] (Preparation of a physical mixture of L-glutamic acid and sucrose (Glu-Suc[PM])) L-glutamic acid and sucrose were mixed in the same molar ratio as Glu-Suc[GM] (L-glutamic acid:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Glu-Suc[PM]").

[0087] (Preparation of Ground Mixture of L-Arginine and Sucrose (Arg-Suc[GM])) A milled mixture (hereinafter also referred to as "Arg-Suc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.670 g (0.00385 mol) of L-arginine and 1.330 g (0.00389 mol) of sucrose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0088] (Preparation of physical mixture of L-arginine and sucrose (Arg-Suc[PM])) L-arginine and sucrose were mixed in the same molar ratio as Arg-Suc[GM] (L-arginine:sucrose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Arg-Suc[PM]").

[0089] (Preparation of Ground Mixture of L-Leucine and Glucose (Leu-Glc[GM])) A milled mixture (hereinafter also referred to as "Leu-Glc[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.840 g (0.00640 mol) of L-leucine and 1.160 g (0.00644 mol) of glucose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0090] (Preparation of a physical mixture of L-leucine and glucose (Leu-Glc[PM])) L-leucine and glucose were mixed in the same molar ratio as Leu-Glc[GM] (L-leucine:glucose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Leu-Glc[PM]").

[0091] (Preparation of a Ground Mixture of L-Leucine and Fructose) An attempt was made to prepare a ground mixture using the same procedure as for Gly-Suc[GM], except that 0.840 g (0.00640 mol) of L-leucine and 1.160 g (0.00644 mol) of fructose were added to the grinding vessel instead of glycine and sucrose, but the ground mixture could not be recovered due to browning and sticking.

[0092] (Preparation of Ground Mixture of L-Leucine and Trehalose (Leu-Tre[GM])) A milled mixture (hereinafter also referred to as "Leu-Tre[GM]") was prepared in the same manner as Gly-Suc[GM], except that 0.550 g (0.00419 mol) of L-leucine and 1.450 g (0.00424 mol) of trehalose were added to the milling container instead of glycine and sucrose. The prepared milled mixture was in powder form and was stored in the same manner as Gly-Suc[GM].

[0093] (Preparation of a physical mixture of L-leucine and trehalose (Leu-Tre[PM])) L-leucine and trehalose were mixed in the same molar ratio as Leu-Tre[GM] (L-leucine:trehalose = 1:1.0), and the resulting mixture was ground in an agate mortar to prepare a physical mixture (hereinafter also referred to as "Leu-Tre[PM]").

[0094] (PXRD analysis) The ground mixtures (Gly-Suc[GM], Val-Suc[GM], Ile-Suc[GM], Cys2-Suc[GM], Tyr-Suc[GM], Glu-Suc[GM], Arg-Suc[GM], Leu-Glc[GM], Leu-Tre[GM]) and physical mixtures (Gly-Suc[PM], Val-Suc[PM], Ile-Suc[PM], Cys2-Suc[PM], Tyr-Suc[PM], Glu-Suc[PM], Arg-Suc[PM], Leu-Glc[PM], Leu-Tre[PM]) obtained above were each analyzed by the PXRD method. As a control for the analysis, the amino acids (glycine, L-valine, L-isoleucine, cystine, L-tyrosine, L-glutamic acid, L-arginine, L-leucine) and sugars (sucrose, glucose, trehalose) used as the raw materials for each ground mixture were analyzed by the PXRD method. The amino acids and sugars were each ground in an agate mortar for about 5 minutes and used in a homogeneous state. The obtained PXRD patterns are shown in Figures 5 to 13.

[0095] As shown in the PXRD patterns of Figures 6 to 8, 11 and 12, no crystalline peaks were detected in Val-Suc[GM], Ile-Suc[GM], Cys2-Suc[GM], Arg-Suc[GM] and Leu-Glc[GM], and halo peaks (broad peaks) were detected. Therefore, it was confirmed that amino acids and sugars form a co-amorphous structure in all of Val-Suc[GM] (a ground mixture of L-valine and sucrose), Ile-Suc[GM] (a ground mixture of L-isoleucine and sucrose), Cys2-Suc[GM] (a ground mixture of cystine and sucrose), Arg-Suc[GM] (a ground mixture of L-arginine and sucrose) and Leu-Glc[GM] (a ground mixture of L-leucine and glucose). On the other hand, as shown in the PXRD pattern in Figure 13, no halo peak was detected in Leu-Tre[GM], and a crystalline peak was detected, confirming that the amino acid and sugar did not form a co-amorphous structure in Leu-Tre[GM] (a ground mixture of L-leucine and trehalose). As shown in the PXRD patterns of Figures 5, 9, and 10, halo peaks were detected in Gly-Suc[GM], Tyr-Suc[GM], and Glu-Suc[GM], but crystalline peaks were also detected to a certain extent. Since the PXRD analysis of Gly-Suc[GM], Tyr-Suc[GM], and Glu-Suc[GM] could not clearly determine whether or not a co-amorphous structure was formed, differential scanning calorimetry (DSC) analysis was performed.

[0096] The analysis by DSC method was carried out under the following conditions. [DSC analysis conditions] Equipment: DSC7000X (Hitachi High-Tech Science Corporation) Nitrogen gas flow rate: 30mL / min Sample container: Crimp an open aluminum container Reference: Empty container Sample size: approx. 4mg Temperature program: -20℃~180℃ at a rate of 10℃ / min

[0097] (DSC analysis) The above ground mixtures (Gly-Suc[GM], Tyr-Suc[GM], Glu-Suc[GM]) and physical mixtures (Gly-Suc[PM], Tyr-Suc[PM], Glu-Suc[PM]) were each analyzed by DSC. In addition, the amino acids (glycine, L-tyrosine, L-glutamic acid) and sugars (sucrose) used as raw materials for each ground mixture were each analyzed by DSC. The amino acids and sugars were each ground in an agate mortar for about 5 minutes and used in a homogenous state. The obtained DSC patterns are shown in Figures 14 to 16.

[0098] As shown in the DSC patterns of Figures 15 and 16, both Tyr-Suc[GM] and Glu-Suc[GM] exhibited both a baseline shift due to glass transition and an exothermic peak due to crystallization. Therefore, it was confirmed that amino acids and sugars form a co-amorphous structure in both Tyr-Suc[GM] (a ground mixture of L-tyrosine and sucrose) and Glu-Suc[GM] (a ground mixture of L-glutamic acid and sucrose). On the other hand, as shown in the DSC pattern in Figure 14, neither a baseline shift nor an exothermic peak was detected in Gly-Suc[GM]. Therefore, it was determined that in Gly-Suc[GM] (a ground mixture of glycine and sucrose), amino acids and sugars did not form a co-amorphous structure.

[0099] <Test Example 3> The water dissolution rate of Leu-Suc[GM1] and Leu-Suc[GM7] prepared in Test Example 1 was confirmed by the following test. For the control of Leu-Suc[GM1], Leu-Suc[PM1] prepared in Test Example 1 was sieved using a sieve with a mesh size of 45 μm to obtain a particle size equal to or smaller than that of Leu-Suc[GM1] (fraction below the sieve), and for the control of Leu-Suc[GM7], Leu-Suc[PM4] prepared in Test Example 1 was sieved using a sieve with a mesh size of 45 μm to obtain a particle size equal to or smaller than that of Leu-Suc[GM7] (fraction below the sieve). The volumetric particle size distributions of Leu-Suc[GM1], Leu-Suc[GM7], Leu-Suc[PM1], and Leu-Suc[PM4] used in the following test are shown in FIG. 17. The particle size distribution was measured by a dry laser diffraction method using a laser diffraction particle size distribution analyzer "HELOS&RODOS / M" manufactured by Sympatec GmbH (measurement range: 4.5 to 875 μm). From the particle size distribution shown in FIG. 17, it was confirmed that the average particle size of the sieved Leu-Suc[PM1] and Leu-Suc[PM4] was equal to or smaller than that of Leu-Suc[GM1] and Leu-Suc[GM7].

[0100] (Water dissolution rate confirmation test) A 100 mL Erlenmeyer flask with the sample powder (Leu-Suc[GM1], Leu-Suc[GM7], Leu-Suc[PM1] or Leu-Suc[PM4]) on the bottom was filled with 100 mL of 50 mM Tris-HCl buffer (pH 7.5) and a stirrer (25 × φ8 mm), and the mixture was stirred at 600 rpm using a stirrer. The amount of sample powder on the bottom of the Erlenmeyer flask was 2.00 g for Leu-Suc[GM1] and Leu-Suc[PM1], and 3.61 g for Leu-Suc[GM7] and Leu-Suc[PM4]. After 1, 3, 5, 10, 30 and 60 minutes from the start of stirring, approximately 1 mL of the solution was sampled from the Erlenmeyer flask and filtered through a 0.45 μm pore size filter (GL Sciences, Inc.) to obtain a supernatant sample. Each sample was diluted 500-fold with 0.02 N hydrochloric acid and then subjected to amino acid analysis to measure the L-leucine concentration. Amino acid analysis was carried out under the following conditions. [Conditions for amino acid analysis] Equipment: High-speed amino acid analyzer L-8900 (Hitachi High-Tech Science Corporation) Separation column: 4.6 mm ID x 60 mm (filler: cation exchange resin #2622 Na + Type) Ammonia column: 4.6mm ID x 40mm (filler: strong acid cation exchange resin #2650L) Reactor temperature: 135℃ Detection wavelength: 440nm Sample injection volume: 25μL The gradient conditions were as shown in Table 2 below. The mobile phases (B1 to B6, R1 to R3) in Table 2 are as follows. The percentages (%) of the mobile phases in Table 2 are based on volume. B1: Hitachi High-Speed ​​Amino Acid Analyzer Buffer Solution PH-1 KANTO (Kanto Chemical Co., Ltd.) B2: Hitachi High-Speed ​​Amino Acid Analyzer Buffer Solution PH-2 KANTO (Kanto Chemical Co., Ltd.) B3: Hitachi High-Speed ​​Amino Acid Analyzer Buffer Solution PH-3 KANTO (Kanto Chemical Co., Ltd.) B4: Hitachi High-Speed ​​Amino Acid Analyzer Buffer Solution PH-4 KANTO (Kanto Chemical Co., Ltd.) B5: Ultrapure water (Milli-Q water) B6: Hitachi High-Speed ​​Amino Acid Analyzer Buffer Solution PH-RG KANTO (Kanto Chemical Co., Ltd.) R1: Ninhydrin solution for Hitachi high-speed amino acid analyzer (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) R2: Hitachi High-Performance Amino Acid Analysis Buffer (FUJIFILM Wako Pure Chemical Industries, Ltd.) R3: 5 vol% ethanol (manufactured by Junsei Chemical Co., Ltd.)

[0101] [Table 2]

[0102] The results are shown in Figures 18 and 19.

[0103] As shown in Figures 18 and 19, the physical mixtures of L-leucine and sucrose (Leu-Suc[PM1] and Leu-Suc[PM4]) required 30 to 60 minutes for the L-leucine concentration to reach a plateau, whereas the ground mixtures of L-leucine and sucrose (Leu-Suc[GM1] and Leu-Suc[GM7]) required 3 to 5 minutes for the L-leucine concentration to reach a plateau. Leu-Suc[PM1] and Leu-Suc[PM4] are co-amorphous structures of L-leucine and sucrose (Test Example 1), and it was confirmed that the water dissolution rate was improved by the formation of a co-amorphous structure of L-leucine and sucrose.

[0104] The water solubility of Cys2-Suc[GM] and Tyr-Suc[GM] prepared in Test Example 2 was confirmed by the following test. For the control of Cys2-Suc[GM], Cys2-Suc[PM] prepared in Test Example 2 was sieved through a sieve with a mesh size of 45 μm to obtain a particle size equal to or smaller than that of Cys2-Suc[GM] (fraction below the mesh size). For the control of Tyr-Suc[GM], Tyr-Suc[PM] prepared in Test Example 2 was sieved through a sieve with a mesh size of 45 μm to obtain a particle size equal to or smaller than that of Tyr-Suc[GM] (fraction below the mesh size).

[0105] (Water solubility confirmation test) A 100 mL Erlenmeyer flask with the sample powder (Cys2-Suc[GM], Cys2-Suc[PM], Tyr-Suc[GM] or Tyr-Suc[PM]) on the bottom was charged with 100 mL of 50 mM Tris-HCl buffer (pH 7.5) and a stir bar (25 × φ8 mm), and stirred at 600 rpm using a stirrer. The amount of sample powder charged on the bottom of the Erlenmeyer flask was 0.1212 g for Cys2-Suc[GM] and Cys2-Suc[PM], and 0.1734 g for Tyr-Suc[GM] and Tyr-Suc[PM]. Approximately 1 mL of the solution was sampled from the Erlenmeyer flask 1, 3, 5, 10, 30, 60, and 120 minutes after the start of stirring, and the supernatant samples were obtained by filtering through a 0.45 μm pore size filter (GL Sciences, Inc.). Each sample was diluted 4-fold with 0.02 N hydrochloric acid and subjected to amino acid analysis to measure the cystine or L-tyrosine concentration. The amino acid analysis was carried out under the same conditions as those for the amino acid analysis in the above-mentioned water dissolution rate confirmation test. The results are shown in Figures 20 and 21.

[0106] As shown in Figure 20, the cystine concentration in the ground mixture of cystine and sucrose (Cys2-Suc[GM]) was increased compared to the physical mixture of cystine and sucrose (Cys2-Suc[PM]). Cys2-Suc[GM] is a mixture of cystine and sucrose that form a co-amorphous structure (Test Example 2), and it was confirmed that the water solubility was improved due to the formation of a co-amorphous structure between cystine and sucrose. In addition, as shown in Figure 21, the L-tyrosine concentration in the ground mixture of L-tyrosine and sucrose (Tyr-Suc[GM]) was increased compared to the physical mixture of L-tyrosine and sucrose (Tyr-Suc[PM]). Tyr-Suc[GM] is a mixture of L-tyrosine and sucrose that form a co-amorphous structure (Test Example 2), and it was confirmed that the water solubility was improved due to the formation of a co-amorphous structure between L-tyrosine and sucrose.

[0107] The results of the above Test Examples 1 to 3 suggest that a specific amino acid (leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, arginine) can form a co-amorphous structure with a specific sugar (sucrose, glucose) by crushing and mixing the specific amino acid and the sugar. It was also suggested that a composition in which a specific amino acid and a specific sugar form a co-amorphous structure can have improved water solubility (water dissolution rate, water dissolution amount). [Industrial Applicability]

[0108] According to the present invention, there is provided a method for improving the water solubility of a specific amino acid or a salt thereof. Since the method of the present invention does not require the use of an organic acid, the water solubility of the specific amino acid or a salt thereof can be improved while suppressing the effect on the pH and taste during dissolution. The present invention also provides a composition containing a specific amino acid or a salt thereof with improved water solubility, and a method for producing the same. The composition of the present invention does not necessarily contain an organic acid, and can suppress the effect on pH and taste when dissolved, so there is no restriction on its use in foods, etc.

Claims

1. (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, and (B) containing at least one sugar selected from the group consisting of sucrose and glucose; A composition, wherein at least a portion of (A) and at least a portion of (B) form a co-amorphous structure.

2. (i) the (A) contains at least leucine or a salt thereof, and the (B) contains at least sucrose; (ii) The (A) contains at least valine or a salt thereof, and the (B) contains at least sucrose; (iii) the (A) contains at least isoleucine or a salt thereof, and the (B) contains at least sucrose; (iv) the (A) contains at least cystine or a salt thereof, and the (B) contains at least sucrose; (v) containing at least tyrosine or a salt thereof as (A) and at least sucrose as (B); (vi) The (A) contains at least glutamic acid or a salt thereof, and the (B) contains at least sucrose; (vii) The (A) contains at least arginine or a salt thereof, and the (B) contains at least sucrose, or (viii) The composition according to claim 1, comprising at least leucine or a salt thereof as (A) and at least glucose as (B).

3. The composition according to claim 1, wherein the molar ratio of (A) and (B) contained in the composition is A:B=1:0.1-10.

4. The composition according to any one of claims 1 to 3, which is a food composition, a pharmaceutical composition, a feed composition, or a cosmetic composition.

5. A method for producing a food, a medicine, an animal feed, or a cosmetic product, comprising using the composition according to any one of claims 1 to 3.

6. A food, medicine, feed or cosmetic product comprising the composition according to any one of claims 1 to 3.

7. The method includes crushing and mixing (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, and (B) at least one sugar selected from the group consisting of sucrose and glucose. A method for producing a composition containing the (A) and the (B), in which at least a portion of the (A) and at least a portion of the (B) form a co-amorphous structure.

8. The method according to claim 7, wherein the grinding and mixing of (A) and (B) is carried out using a ball mill.

9. (i) at least leucine or a salt thereof is used as (A) and at least sucrose is used as (B); (ii) at least valine or a salt thereof is used as (A) and at least sucrose is used as (B); (iii) at least isoleucine or a salt thereof is used as (A) and at least sucrose is used as (B); (iv) at least cystine or a salt thereof is used as (A) and at least sucrose is used as (B); (v) using at least tyrosine or a salt thereof as (A) and at least sucrose as (B); (vi) at least glutamic acid or a salt thereof is used as (A) and at least sucrose is used as (B); (vii) at least arginine or a salt thereof is used as (A) and at least sucrose is used as (B), or (viii) The method according to claim 7, wherein at least leucine or a salt thereof is used as (A), and at least glucose is used as (B).

10. The method according to claim 7, wherein the molar ratio of (A) and (B) to be ground and mixed is A:B=1:0.1-10.

11. The method according to any one of claims 7 to 10, wherein the composition is a food composition, a pharmaceutical composition, a feed composition, or a cosmetic composition.

12. A method for producing a food, a medicine, an animal feed or a cosmetic product, comprising using a composition obtained by the method according to any one of claims 7 to 10.

13. A method for improving the water solubility of (A), comprising grinding and mixing (A) at least one amino acid or a salt thereof selected from the group consisting of leucine, valine, isoleucine, cystine, tyrosine, glutamic acid, and arginine, together with (B) at least one sugar selected from the group consisting of sucrose and glucose, to form a co-amorphous structure between at least a portion of (A) and at least a portion of (B).

14. The method according to claim 13, wherein the grinding and mixing of (A) and (B) is carried out using a ball mill.

15. (i) at least leucine or a salt thereof is used as (A) and at least sucrose is used as (B); (ii) at least valine or a salt thereof is used as (A) and at least sucrose is used as (B); (iii) at least isoleucine or a salt thereof is used as (A) and at least sucrose is used as (B); (iv) at least cystine or a salt thereof is used as (A) and at least sucrose is used as (B); (v) using at least tyrosine or a salt thereof as (A) and at least sucrose as (B); (vi) at least glutamic acid or a salt thereof is used as (A) and at least sucrose is used as (B); (vii) at least arginine or a salt thereof is used as (A) and at least sucrose is used as (B), or (viii) The method according to claim 13 or 14, wherein at least leucine or a salt thereof is used as (A), and at least glucose is used as (B).

16. The method according to claim 13 or 14, wherein the molar ratio of (A) and (B) to be ground and mixed is A:B=1:0.1-10.

17. The method according to claim 13 or 14, wherein the improvement in the water solubility of the component (A) is an improvement in the water dissolution rate and / or the water dissolution amount of the component (A).

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