WO2021187472A1 - Mixture of organic acid and amino group-containing compound forming amorphous structure - Google Patents

Mixture of organic acid and amino group-containing compound forming amorphous structure Download PDF

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WO2021187472A1
WO2021187472A1 PCT/JP2021/010576 JP2021010576W WO2021187472A1 WO 2021187472 A1 WO2021187472 A1 WO 2021187472A1 JP 2021010576 W JP2021010576 W JP 2021010576W WO 2021187472 A1 WO2021187472 A1 WO 2021187472A1
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acid
amino acid
mixture
organic acid
mixture according
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Japanese (ja)
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洵 洗
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味の素株式会社
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/20—Synthetic spices, flavouring agents or condiments
    • A23L27/21—Synthetic spices, flavouring agents or condiments containing amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • the present invention relates to a mixture that suppresses (reduces) the bitterness of an orally ingested composition such as foods and drinks and oral pharmaceuticals, and a method for producing an orally ingested composition that suppresses (reduces) the bitterness.
  • Branched chain amino acids such as valine, leucine, and isoleucine are known to exhibit bitterness, and as a technique for suppressing the bitterness of foods and drinks and oral drugs containing BCAA, for example, Patent Document 1 discloses a technique for blending a ⁇ -glutamyl peptide, and Patent Document 2 discloses a technique for coating with fats and oils. Peptides are more expensive than amino acids and affect manufacturing costs. In addition, fat coating is limited to applications where fats and oils can be tolerated.
  • Patent Document 4 discloses a technique for blending peptides.
  • peptides have a problem of increasing the production cost.
  • Patent Document 5 discloses that when a product containing an acidulant is manufactured in order to suppress the bitterness of amino acids, it may not dissolve in the oral cavity and may feel rough.
  • the problem to be solved by the present invention is to provide a means capable of masking the unpleasant taste of foods and drinks and oral pharmaceuticals without using expensive peptides, with few restrictions on uses and compositions, and with less labor for production. It is in.
  • the present invention has been made to solve the above problems, in which an amino group-containing compound and an organic acid form a co-amorphous structure, and the co-amorphous structure suppresses an unpleasant taste more than a simple mixture. I found out to do. Even more surprisingly, it was found that it has the effect of increasing the dissolution rate and quickly dissolving substances with difficulty in solubility in the mouth or water while suppressing the unpleasant taste.
  • the present invention (1) A mixture of an amino group-containing compound and an organic acid, characterized in that the amino group-containing compound and the organic acid have a co-amorphous structure.
  • the amino group-containing compound is a peptide or an amino acid.
  • the amino group-containing compound is an amino acid selected at least from the group consisting of leucine, isoleucine, valine, cystine, phenylalanine, tyrosine, tryptophan, arginine, and histidine.
  • the amino group-containing compound is an amino acid, and the amino acid is an amino acid exhibiting a bitter taste
  • the amino group-containing compound is a peptide, and the peptide is a dipeptide.
  • the mixture according to (2) (8)
  • the peptide is N-L- ⁇ -aspartyl-L.
  • the organic acid is citric acid, tartrate acid, malic acid, phthalic acid, fumaric acid or succinic acid, or a salt or hydration of each.
  • the present invention also provides.
  • Beverage characterized by containing the mixture according to any one of (1) to (13)
  • a seasoning characterized by containing the mixture according to any one of (1) to (13).
  • a sweetener (17) which comprises the mixture according to any one of (1) to (13). It also provides an oral preparation comprising the mixture according to any one of (18) (1) to (13).
  • N-L- ⁇ -aspartyl-L-phenylalanine 1-methyl is known as a harmless sweetener, but has a strange taste such that the sweetness remains longer than that of sugar. ..
  • the present invention has found that the above-mentioned mixture having a co-amorphous structure has an action of masking these bitterness and / or off-taste.
  • the present invention is an edible product (20) (1)-(13) masked with bitterness and / or off-taste, which comprises the mixture according to any one of (19) (1)-(13).
  • An edible powder product masked with bitterness and / or off-taste which comprises the mixture according to any one of (21) Bitter amino acids and organic acids in a molar ratio of 4: 6 to 6: 4.
  • the amino acid and the organic acid have a molar ratio of 1: 1.
  • NL- is characterized in that a mixture containing N-L- ⁇ -aspartyl-L-phenylalanine 1-methyl and an organic acid in a molar ratio of 1: 1 has a co-amorphous structure.
  • An edible product that masks the off-taste of ⁇ -aspartyl-L-phenylalanine 1-methyl (24) The bitterness of amino acids, which is a mixture of bitter amino acids and organic acids having a co-amorphous structure.
  • Masking Method (25) N-L- ⁇ -Aspartyl-N-L- ⁇ -Aspartyl-, which is a mixture of N-L- ⁇ -aspartyl-L-phenylalanine 1-methyl and an organic acid having a co-amorphous structure. It also provides a method of masking the off-taste of L-phenylalanine 1-methyl.
  • the present invention further (26) A bitter taste having a co-amorphous structure, which comprises an amino acid and an organic acid exhibiting a bitter taste, the amino acid and the organic acid have a molar ratio of 1: 1 and the amino acid and the organic acid are pulverized and mixed by a ball mill.
  • Method for producing a mixture of an amino acid exhibiting a bitter taste and an organic acid (27) A aqueous solution of an amino acid and an aqueous solution of an organic acid containing an amino acid and an organic acid exhibiting a bitter taste are mixed at a molar ratio of 1: 1 and spray-dried at a temperature of 130 ° C. or higher.
  • (A) has a co-amorphous structure, which comprises B), has a molar ratio of (A) and (B) of 1: 1, and is characterized by pulverizing and mixing (A) and (B) with a ball mill.
  • the "unpleasant taste” refers to an unpleasant taste and flavor that cannot be felt when ordinary foods and pharmaceuticals are orally ingested, and specific examples thereof include bitterness, astringency, spiciness, harshness, and roughness. Be done. The presence or absence and degree of unpleasant taste can be evaluated by sensory evaluation as shown in Examples described later.
  • Both the amino acids and organic acids used in the present invention usually exist as crystals. This is because the amorphous substances of these simple substances are unstable, and if left untreated, they will be transferred to crystals. Molecules are regularly arranged in a crystal to form a crystal lattice. On the other hand, amorphous does not have a long-range order such as a crystal lattice, and has a very low interaction for stabilizing a solid state such as lattice energy, so that it disperses and hydrates more easily than a crystal and has a faster dissolution rate.
  • Amino acid crystals are amorphized by applying high impact force and shearing force when crushed with a ball mill. At that time, if an organic acid is allowed to exist as a counter substance, it is considered that the organic acid has a high affinity with amino acids and stabilizes the state of the amorphous structure. In the co-amorphous structure of the present invention, since the hydrophilicity of the organic acid is high, it is considered that water can easily enter the co-amorphous structure of a normal amino acid alone, and the dissolution rate and the dissolution amount are further improved. Be done.
  • the present inventor dissolves a co-amorphous structure formed by amino acids of the earlier patent application (Japanese Patent Application No. 2019-117131), for example, a co-amorphous structure of tyrosine and arginine in water.
  • a co-amorphous structure formed by amino acids of the earlier patent application (Japanese Patent Application No. 2019-117131), for example, a co-amorphous structure of tyrosine and arginine in water.
  • tyrosine having a co-amorphous structure has a high kinetic solubility as compared with the thermodynamic solubility of ordinary crystalline tyrosine, and the tyrosine concentration is considerably high. Nevertheless, it was found that it was stably dissolved without crystallizing.
  • FIG. 6 compares the supernatant cystine concentration of a co-amorphous structure containing an equimolar amount of cystine and citric acid and a crystal mixture obtained by an equimolar mixture of cystine and citric acid crystals.
  • the co-amorphous structure has a higher dissolution rate than the crystalline mixture.
  • the co-amorphous structure is structurally unstable as compared with the crystal, and the lattice energy is low, so that the co-amorphous structure is easily dissolved. This is generally recognized in the pharmaceutical industry as the solubility of crystals is called kinetic solubility and the solubility of amorphous structures is called thermodynamic solubility.
  • the reason why the co-amorphous structure shown in FIG. 6 is stable at a higher supernatant cystine concentration than the crystal is that the co-amorphous structure is more stable than the crystal when it is precipitated as a crystal. This is because it takes a long time to precipitate. When crystals dissolve, they form aggregates that retain their crystal structure in water, whereas co-amorphous structures do not have a crystal structure, so they form completely random aggregates in water. It is necessary to transfer from a random aggregate to an aggregate having a crystal structure, and the transition takes a long time.
  • solid solutions of three kinds of amino acids such as valine, leucine and isoleucine are also known (WO2010 / 050168), and it is also known that the dissolution rates of these solid solutions of valine, leucine and isoleucine are improved.
  • a solid solution is one in which a part of the crystal lattice is replaced with another molecule or another molecule is inserted between the crystal lattices, that is, it is a crystal and has a random structure like an amorphous substance.
  • the dissolution rate of the solid solution is much slower than that of the co-amorphous structure of the present invention, and the effect of improving bitterness and the like is also inferior.
  • the mixture of the amino acid-containing compound having a co-amorphous structure and the organic acid of the present invention can significantly increase the dissolution rate of the amino group-containing compound, and even a poorly soluble compound can be easily dissolved.
  • the bitterness and the like of the amino group-containing compound can be masked to eliminate the aftertaste or improve the melting feeling in the mouth.
  • FIG. 5 is a powder X-ray diffraction diagram of a mixture of various amino acids and a counter substance obtained in Example 1. It is a graph which shows the dissolution test result of a Leu-citric acid co-amorphous substance and a Leu + citric acid crystal. It is a graph which shows the dissolution test result of a Leu-Arg co-amorphous substance and a Leu + Arg crystal. It is a graph which shows the dissolution test result of Val-citric acid co-amorphous substance and Val + citric acid crystal. It is a graph which shows the dissolution test result of Ile-citric acid co-amorphous substance and Ile + citric acid crystal.
  • FIG. 5 is a powder X-ray diffraction diagram of a mixture of cystine and various organic acids obtained in Example 3. It is a powder X-ray diffraction diagram of the mixture of various amino acids and citric acid obtained in Example 4.
  • FIG. 5 is a powder X-ray diffraction diagram of a mixture of N-L- ⁇ -aspartyl-L-phenylalanine 1-methyl and various organic acids obtained in Example 5. It is a graph which schematically explains the dissolution behavior of a crystal and an amorphous.
  • the mixture of the present invention has an amorphous structure of an amino group-containing compound and an organic acid.
  • Amino group-containing compounds are, for example, amino acids and peptides.
  • Amino acids are represented by R-CH (NH 2 ) COOH, where R is a hydrogen group, an alkyl group having 1 to 5 carbon atoms, a hydroxyl group, an amino group, a carboxyl group, an aromatic ring, a sulfide bond, a disulfide bond, and a thiol group. And / or those comprising at least one group selected from the group consisting of groups comprising a cyclic structure.
  • the amino acid in which R is a hydrogen group is glycine
  • the amino acid in which an alkyl group having 1 to 5 carbon atoms is an alkyl group may be alanine or a branched chain amino acid such as valine, leucine or isoleucine.
  • the amino acid containing a hydroxyl group may be serine, threonine or the like
  • the amino acid containing an amino group may be lysine, arginine, ornithine, glutamine, aspartic acid or the like
  • the amino acid containing a carboxyl group may be aspartic acid, glutamic acid or the like. It may be.
  • the amino acid containing an aromatic ring may be phenylalanine, tyrosine or the like, the amino acid containing a sulfide or disulfide bond may be methionine, cystine or the like, and the amino acid containing a thiol group may be cysteine or the like.
  • the amino acid containing a cyclic structure may contain a heterocycle such as histidine, tryptophan, proline, or hydroxyproline. Imino acids such as proline and hydroxyproline may also be included in the amino acids of the present invention.
  • One of the objects of the present invention is to make it possible to easily dissolve a poorly soluble amino acid.
  • Poorly soluble amino acids include those with low solubility such as cystine, tyrosine, and tryptophan, and those with solubility itself such as phenylalanine, valine, leucine, and isoleucine, but their side chains are hydrophobic, so they should be added to water.
  • the co-amorphous structure of the present invention is to improve the solubility of these amino acids because some of them have low affinity with water and cannot be easily dissolved.
  • these branched-chain amino acids and phenylalanine, tryptophan, arginine, tyrosine, histidine, etc. are also known as amino acids that exhibit a bitter taste, and cystine, etc., feels grainy when put in the mouth. Since it is known that the co-amino acid structure of the present invention masks these bitterness and graininess, and eliminates the graininess to improve the melting feeling in the mouth.
  • Peptides are amino acids linked by peptide bonds, and depending on the number of bonds, there are dipeptides, tripeptides, etc., but peptides or ester derivatives of peptides in which the carboxyl group at the end of the peptide is a methyl ester, etc. are also organic acids. Can be a co-amorphic structure. Examples of peptides include branched chain amino acid peptides such as glycomacropeptide, dileucine, and trileucine.
  • the dipeptide N-L- ⁇ -aspartame-L-phenylalanine 1-methyl (trade name "aspartame”, abbreviated as AP) is known as a non-toxic sweetener, but has a residual sweetness. It was found that when this was made into the co-amorphous structure of the present invention, the aftertaste was reduced and the taste became closer to that of sugar.
  • organic acids such as sulfonic acid and phenol in addition to carboxylic acid excluding amino acids, but carboxylic acid is particularly desirable.
  • This organic acid forms a co-amorphous structure with the amino group-containing compound.
  • carboxylic acids include citric acid, tartaric acid, malic acid, succinic acid, phthalic acid, fumaric acid and the like.
  • the organic acid may be a hydrate or may be in the form of a salt such as an iron salt or a sodium salt. For example, it may be sodium ferrous citrate.
  • the combination of the amino group-containing compound and the organic acid may be any combination as long as it can form a co-amorphous structure.
  • the mixing ratio of the amino group-containing compound and the organic acid in the mixture with the co-amorphous structure of the present invention may be as long as the co-amorphous structure can be formed, for example, in a molar ratio of 1: 0.1 to 1:10. It is often, preferably 1: 0.2 to 1: 5, preferably 1: 0.5 to 1: 2, more preferably 1: 0.6 to 1: 2, and even more preferably 6: It is 4 to 4: 6, and most preferably 1: 1 in molar ratio.
  • the molar ratio may be 1: 1, but the molar ratio is not limited to this, as long as a co-amorphous structure can be formed.
  • the molar ratio may be 6: 4.
  • the amino group-containing compound and the organic acid of the present invention have a co-amorphous structure, but in the co-amorphous structure, the amino group-containing compound and the organic acid interact with each other to maintain an amorphous state. It is a structure, and both are uniformly dispersed and mixed. If a method of dissolving and solidifying an amino group-containing compound and an organic acid, for example, a spray-drying method, a melt quenching method (hot melt method), or a freeze-drying method, both are in a solidified state of the solution, that is, a molecular unit. If you use the method of mixing and grinding the powder as it is, for example, the method of grinding with a ball mill, both will become fine powder and will be in a state of being mixed in molecular units as a solid. ..
  • Whether or not the amino group-containing compound and the organic acid have a co-amorphous structure can be confirmed by a known method such as X-ray diffraction method or Raman spectroscopy.
  • the mixture of the present invention suffices if the amino group-containing compound and the organic acid have a co-amorphous structure, and has a co-amorphous structure of three or more kinds including other amino group-containing compounds and an organic acid. May be good.
  • third components other than organic acids, salts thereof and other components may be contained.
  • the co-amorphous structure with an amino group-containing compound or an organic acid of the present invention is a known method for producing an amorphous body of an amino group-containing compound or an organic acid, for example, a method of grinding using a ball mill, for example. It can be produced by a spray drying (spray granulation) method using a spray dryer, a melt quenching method, a freeze drying method, or the like.
  • the amino group-containing compound and the organic acid may be added at a predetermined mixing ratio, and if necessary, a pulverizing aid may be added to pulverize and mix until a co-amorphous structure is formed.
  • the amino group-containing compound and the organic acid to be added may be either crystalline or amorphous, but are usually crystalline.
  • the pulverization aid is added to prevent solidification of the amino group-containing compound and the organic acid during pulverization, and ethanol or the like is preferably added in an amount of about 0.1 to 5% by mass based on the total amount of the amino group-containing compound and the organic acid.
  • the pulverization conditions are until the amino group-containing compound and the organic acid have a co-amorphous structure, but usually, the rotation speed of the ball mill may be 200 to 1200 rpm for about 1 to 12 hours. Since the temperature of the ball mill rises during pulverization, it is preferable to cool the pot of the ball mill to less than 15 ° C, preferably 5 to 15 ° C. Grinding aids such as ethanol volatilize during milling and do not remain in the mixture. In addition, planetary ball mills (Kurimoto Iron Works Co., Ltd.), Atwriter (Nippon Coke Industries Co., Ltd.), and Simoroyer (Zoz GmbH) can also be used as ball mills.
  • an aqueous solution containing an amino group-containing compound and an organic acid in a predetermined mixing ratio is prepared, and spray-dried at a temperature of 130 ° C. or higher, preferably 160 ° C. or higher.
  • the co-amorphous structure of the amino group-containing compound and the organic acid of the present invention has an effect of masking the bitterness and unpleasant taste of the amino acid-containing compound, and is therefore useful as a masking method for these.
  • the bittersweet amino group-containing compound include amino acids such as valine, leucine, isoleucine, phenylalanine, tryptophan, arginine, tyrosine, and histidine.
  • cystine has a rough feel due to the feeling of biting sand when it is put in the mouth, but the co-amorphous structure of the present invention eliminates this rough feeling and improves the melting in the mouth, so it can also be used as a masking method. It is useful.
  • N-L- ⁇ -aspartyl-L-phenylalanine 1-methyl and the like are known as harmless sweeteners, but have a different taste in which the sweetness remains for a long time. However, when this is made into the co-amorphous structure of the present invention, the sweetness disappears quickly and the unpleasant sensation disappears. Therefore, it is also useful as a masking method for eliminating the unpleasant taste of sweetness of such dipeptides.
  • the uses of the present invention are not limited in any way, but a mixture of an amino group-containing compound and an organic acid having a co-amorphous structure can be used for new uses or contains conventionally used amino groups. It can be replaced with a compound, an inorganic compound or an organic acid.
  • examples of this application include various beverages, sweeteners, seasonings, beverage powders, health foods, oral medicines, media and the like.
  • Edible products are compositions that are taken orally or used in the oral cavity, and include foods, seasonings, pharmaceuticals, non-pharmaceutical products, and cosmetics, and edible powder products include these. It is a powder, for example, a product (powder for sports drinks) in which the powder is dissolved in water to make a beverage.
  • Example 1 (1) Preparation of Amino Acid / Counter Co-Amorphous Mixture Leucine (manufactured by Ajinomoto Co., Inc.) 4.06 g (0.031 mol), citric acid (manufactured by Fuji Film Wako Chemical Co., Ltd.) 5.94 g (0.031 mol) And 0.4 mL of ethanol as a pulverizing aid was placed in a 125 mL pot made of zirconia. 50 zirconia 10 mm balls were placed in a pot and set in a ball mill (Vader Scientific, Lecce Emax). A cooling water of 15 ° C. was flowed around the outer periphery of the pot at a rotation speed of 1000 rpm, and pulverization and mixing were carried out at a pulverization temperature of about 28 ° C. for 6 hours to obtain 9.1 g of powder.
  • Leucine manufactured by Ajinomoto Co., Inc.
  • citric acid manufactured by Fuji Film Wako Chemical
  • Amino acids and counter substances were changed to the second and subsequent substances in Table 1 to prepare an amorphous mixture in the same manner, and a powder of the mixture was obtained.
  • the amino acids and counter substances were changed to the second and subsequent substances in Table 2, and the dissolution amount confirmation test was conducted in the same manner, and the results shown in FIGS. 3 to 5 were obtained. From this, it was confirmed that the solids of Leu-Arg, Val-citric acid, and Ile-citric acid obtained in (1) dissolve faster than the crushed crystals.
  • Example 2 Conducted using cystine (Cys2) (manufactured by Ajinomoto Co., Inc.) 5.56 g (0.027 mol), citric acid (manufactured by Fujifilm Wako Chemical Co., Ltd.) 4.44 g (0.027 mol) and 0.2 ml of ethanol as a pulverizing aid. The same pulverization and mixing as in (1) of Example 1 was carried out to obtain 9.7 g of powder.
  • cystine Cys2
  • citric acid manufactured by Fujifilm Wako Chemical Co., Ltd.
  • Example 3 Using cystine (Cys2) (manufactured by Ajinomoto Co., Inc.), the organic acid shown in Table 4, and 0.2 ml of ethanol as a pulverizing aid, pulverization and mixing were carried out in the same manner as in (1) of Example 1 to obtain a powder.
  • This solid was used in the same manner as in (2) of Example 1 to obtain a powder X-ray diffraction pattern. The obtained results are shown in FIG. It was confirmed that none of the powders had a clear peak peculiar to crystals and was an amorphous powder.
  • Example 4 Amino acids (manufactured by Ajinomoto Co., Inc.), organic acids shown in Table 5, and 0.2 ml of ethanol as a pulverizing aid were used and pulverized and mixed in the same manner as in (1) of Example 1 to obtain a powder. This solid was used in the same manner as in (2) of Example 1 to obtain a powder X-ray diffraction pattern. The obtained results are shown in FIG. It was confirmed that none of the powders had a clear peak peculiar to crystals and was an amorphous powder.
  • Example 5 Example 1 using N-L- ⁇ -aspartame-L-phenylalanine 1-methyl (trade name "aspartame” AP) manufactured by Ajinomoto Co., Inc.), the organic acid shown in Table 6, and 0.2 ml of ethanol as a pulverizing aid.
  • the powder was obtained by pulverizing and mixing in the same manner as in (1). This solid was used in the same manner as in (2) of Example 1 to obtain a powder X-ray diffraction pattern. The obtained results are shown in FIG. It was confirmed that the powder obtained by mixing fumaric acid and citric acid with AP was an amorphous powder without a clear peak peculiar to crystals.
  • the powder obtained by pulverizing and mixing AP and citric acid exhibited a refreshing sweetness thanks to citric acid, with the off-flavor masked and almost no aftertaste.
  • the powder obtained by pulverizing and mixing AP with malic acid, tartaric acid, and succinic acid was not found to be amorphous.
  • Example 6 Production by spray drying When 4.00 g of leucine and 5.85 g of citric acid were dissolved in 120 g of water and spray-dried at a temperature of 170 ° C., 4.2 g of co-amorphous of leucine and citric acid was obtained.
  • the co-amorphous structure of the present invention not only has good solubility of amino group-containing compounds such as amino acids and peptides, which are constituents thereof, but also has a masking effect such as bitterness and off-taste, and is an amino group-containing compound.
  • amino group-containing compounds such as amino acids and peptides, which are constituents thereof, but also has a masking effect such as bitterness and off-taste, and is an amino group-containing compound.

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Abstract

The present invention provides a means that can mask the odd taste of dipeptide sweeteners and the bitterness of amino acids, that increases the dissolution rate of amino acids, that involves less time and effort during production, that has less restrictions regarding the compositional makeup and use application, and that does not use expensive peptides. This mixture is characterized in that an amorphous structure is formed by an organic acid and an amino group-containing compound, and is particularly characterized in that the amino group-containing compound is a peptide or an amino acid.

Description

共非晶質構造を有するアミノ基含有化合物と有機酸の混合物A mixture of an amino group-containing compound having a co-amorphous structure and an organic acid
　本発明は、飲食品や経口医薬品等の経口摂取組成物の苦味を抑制（低減）する混合物および苦味の抑制（低減）された経口摂取組成物の製造方法に関するものである。 The present invention relates to a mixture that suppresses (reduces) the bitterness of an orally ingested composition such as foods and drinks and oral pharmaceuticals, and a method for producing an orally ingested composition that suppresses (reduces) the bitterness.
　アミノ基を含有する有機化合物には優れた機能を持つために飲食物や経口医薬品に利用される物質は多いが、なかには苦みや後味やざらつき感などの異味を呈することのある物質が存在するため、その異味を低減する技術が求められている。 Many organic compounds containing amino groups are used in foods and drinks and oral medicines because they have excellent functions, but some substances may have a different taste such as bitterness, aftertaste, and roughness. , There is a demand for a technique for reducing the unpleasant taste.
　バリン、ロイシン、イソロイシン等の分岐鎖アミノ酸（Branched　chain　amino　acid；ＢＣＡＡ）は、苦味を呈することが知られており、ＢＣＡＡを含有する飲食品や経口医薬品の苦味を抑制する技術としては、たとえば、特許文献1ではγ－グルタミルペプチドを配合する技術が開示されており、特許文献２では油脂でコーティングする技術が開示されている。ペプチド類はアミノ酸以上に高価であり製造コストに影響する。また、油脂コーティングは油脂を許容できる用途に限定される。 Branched chain amino acids (BCAA) such as valine, leucine, and isoleucine are known to exhibit bitterness, and as a technique for suppressing the bitterness of foods and drinks and oral drugs containing BCAA, for example, Patent Document 1 discloses a technique for blending a γ-glutamyl peptide, and Patent Document 2 discloses a technique for coating with fats and oils. Peptides are more expensive than amino acids and affect manufacturing costs. In addition, fat coating is limited to applications where fats and oils can be tolerated.
　Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルなどのジペプチドなどの甘味料についても異味を低減する技術が求められており、特許文献４ではペプチドを配合する技術が開示されている。しかし、ペプチド類は製造コストを増加させる課題がある。 A technique for reducing the unpleasant taste of sweeteners such as dipeptides such as N-L-α-aspartyl-L-phenylalanine 1-methyl is also required, and Patent Document 4 discloses a technique for blending peptides. However, peptides have a problem of increasing the production cost.
　さらに、特許文献５ではアミノ酸の苦みを抑制するために酸味料を配合した製品を製造したところ、口腔内での口溶けが悪くざらつきを感じる場合があることを開示している。 Further, Patent Document 5 discloses that when a product containing an acidulant is manufactured in order to suppress the bitterness of amino acids, it may not dissolve in the oral cavity and may feel rough.
特開２０１６－１７１７６１JP 2016-171761 ＷＯ２０１７－１５９７０８WO2017-159708 特開２０１１－１０３７９９JP 2011-103799 ＷＯ２００８－１３９９４６WO 2008-139946 特開２０１８－１５４５９８JP-A-2018-154598
　本発明が解決しようとする課題は、高価なペプチドを使用せず、また、用途や組成の制限が少なく、しかも製造の手間も少ない、飲食物や経口医薬品の異味をマスキングできる手段を提供することにある。 The problem to be solved by the present invention is to provide a means capable of masking the unpleasant taste of foods and drinks and oral pharmaceuticals without using expensive peptides, with few restrictions on uses and compositions, and with less labor for production. It is in.
　本発明は、上記課題を解決するべくなされたものであり、アミノ基含有化合物と有機酸とが共非晶質構造体になること、および共非晶質構造体が単なる混合物よりも異味を抑制することを見出した。さらに驚くべきことに溶解速度を増加させ、溶解性に難のある物質について異味を抑制したまま口中や水中に素早く溶かす効果があることを見出した。 The present invention has been made to solve the above problems, in which an amino group-containing compound and an organic acid form a co-amorphous structure, and the co-amorphous structure suppresses an unpleasant taste more than a simple mixture. I found out to do. Even more surprisingly, it was found that it has the effect of increasing the dissolution rate and quickly dissolving substances with difficulty in solubility in the mouth or water while suppressing the unpleasant taste.
　すなわち本発明は、
（１）アミノ基含有化合物と有機酸とが共非晶質構造になっていることを特徴とする、アミノ基含有化合物と有機酸の混合物
（２）アミノ基含有化合物が、ペプチドまたはアミノ酸であることを特徴とする（１）に記載の混合物
（３）アミノ基含有化合物が、ロイシン、イソロイシン、バリン、シスチン、フェニルアラニン、チロシン、トリプトファン、アルギニン、ヒスチジンからなる群から少なくとも一つ選択されるアミノ酸であることを特徴とする（２）に記載の混合物
（４）アミノ基含有化合物がアミノ酸であり、該アミノ酸が分岐鎖アミノ酸であることを特徴とする（２）に記載の混合物
（５）分岐鎖アミノ酸が、ロイシン、イソロイシンまたはバリンであることを特徴とする（４）に記載の混合物
（６）アミノ基含有化合物がアミノ酸であり、該アミノ酸が、苦味を呈するアミノ酸であることを特徴とする（２）に記載の混合物
（７）アミノ基含有化合物がペプチドであり、該ペプチドがジペプチドであることを特徴とする（２）に記載の混合物
（８）ペプチドがＮ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルであることを特徴とする（２）に記載の混合物
（９）有機酸が、クエン酸、酒石酸、リンゴ酸、フタル酸、フマル酸もしくはコハク酸または、それぞれの塩もしくは水和物であることを特徴とする（１）または（２）に記載の混合物
（１０）有機酸がクエン酸第一鉄またはその塩であることを特徴とする（９）に記載の混合物
（１１）アミノ基含有化合物がロイシン、イソロイシンまたはバリンであるアミノ酸であり、有機酸がクエン酸、酒石酸またはリンゴ酸であることを特徴とする（２）に記載の混合物
（１２）アミノ酸がロイシンであり、有機酸がクエン酸であることを特徴とする（１１）に記載の混合物
（１３）アミノ酸がチロシンであることを特徴とする（１０）に記載の混合物
を提供するものである。 That is, the present invention
(1) A mixture of an amino group-containing compound and an organic acid, characterized in that the amino group-containing compound and the organic acid have a co-amorphous structure. (2) The amino group-containing compound is a peptide or an amino acid. The mixture according to (1), (3) the amino group-containing compound is an amino acid selected at least from the group consisting of leucine, isoleucine, valine, cystine, phenylalanine, tyrosine, tryptophan, arginine, and histidine. The mixture according to (2) according to (2), the mixture according to (2), wherein the amino group-containing compound is an amino acid, and the amino acid is a branched amino acid. The mixture according to (4), wherein the amino acid is leucine, isoleucine or valine (6) The amino group-containing compound is an amino acid, and the amino acid is an amino acid exhibiting a bitter taste ( 2) The mixture according to (7) The amino group-containing compound is a peptide, and the peptide is a dipeptide. The mixture according to (2) (8) The peptide is N-L-α-aspartyl-L. -The mixture according to (2), which is phenylalanine 1-methyl, (9) the organic acid is citric acid, tartrate acid, malic acid, phthalic acid, fumaric acid or succinic acid, or a salt or hydration of each. The mixture according to (1) or (2) according to (1) or (2) the mixture according to (10) according to (9), wherein the organic acid is ferrous citrate or a salt thereof. The mixture according to (2), wherein the amino group-containing compound is an amino acid such as leucine, isoleucine or valine, and the organic acid is citric acid, tartaric acid or malic acid. The mixture according to (11), wherein the acid is citric acid (13) The mixture according to (10), which is characterized by the amino acid being tyrosine.
　そして、上記で得られた共非晶質構造の混合物はいずれも水溶性が改善されていて、飲料、調味料、甘味料、培地に使用することができるから、本発明は、また、
（１４）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする飲料
（１５）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする調味料
（１６）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする甘味料
（１７）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする培地
（１８）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする経口医薬品
を提供するものでもある。 And since all the mixtures having the co-amorphous structure obtained above have improved water solubility and can be used for beverages, seasonings, sweeteners, and media, the present invention also provides.
(14) Beverage characterized by containing the mixture according to any one of (1) to (13) (15) A seasoning characterized by containing the mixture according to any one of (1) to (13). A sweetener (17), which comprises the mixture according to any one of (1) to (13). It also provides an oral preparation comprising the mixture according to any one of (18) (1) to (13).
　ところで、アミノ酸には苦味があるが、一方、Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルは無害な甘味料として知られているが、甘味が砂糖より長く残るなどの異味感がある。本発明は、上記の共非晶質構造の混合物は、これらの苦味および／または異味をマスキングする作用があることを見出した。 By the way, amino acids have a bitter taste, while N-L-α-aspartyl-L-phenylalanine 1-methyl is known as a harmless sweetener, but has a strange taste such that the sweetness remains longer than that of sugar. .. The present invention has found that the above-mentioned mixture having a co-amorphous structure has an action of masking these bitterness and / or off-taste.
　従って、本発明は
（１９）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする苦味および／または異味をマスキングされた可食性製品
（２０）（１）～（１３）のいずれかに記載の混合物を含むことを特徴とする苦味および／または異味をマスキングされた可食性粉末製品
（２１）苦みを呈するアミノ酸と有機酸がモル比４：６～６：４で含まれる混合物が共非晶質構造になっていることを特徴とするアミノ酸の苦味をマスキングする可食性製品
（２２）アミノ酸と有機酸がモル比１：１である（２１）に記載の可食性製品
（２３）Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルと有機酸がモル比１：１で含まれる混合物が共非晶質構造になっていることを特徴とする、Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルの異味をマスキングする可食性製品
（２４）苦みを呈するアミノ酸と有機酸が共非晶質構造になっている混合物であることを特徴とするアミノ酸の苦味をマスキングする方法
（２５）Ｎ－Ｌ－α-アスパルチル－Ｌ－フェニルアラニン１－メチルと有機酸が共非晶質構造になっている混合物であることを特徴とする、Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルの異味をマスキングする方法
をも提供するものである。 Therefore, the present invention is an edible product (20) (1)-(13) masked with bitterness and / or off-taste, which comprises the mixture according to any one of (19) (1)-(13). An edible powder product masked with bitterness and / or off-taste, which comprises the mixture according to any one of (21) Bitter amino acids and organic acids in a molar ratio of 4: 6 to 6: 4. (22) An edible product according to (21), wherein the mixture is a co-amorphous structure and masks the bitterness of an amino acid. The amino acid and the organic acid have a molar ratio of 1: 1. (23) NL- is characterized in that a mixture containing N-L-α-aspartyl-L-phenylalanine 1-methyl and an organic acid in a molar ratio of 1: 1 has a co-amorphous structure. An edible product that masks the off-taste of α-aspartyl-L-phenylalanine 1-methyl (24) The bitterness of amino acids, which is a mixture of bitter amino acids and organic acids having a co-amorphous structure. Masking Method (25) N-L-α-Aspartyl-N-L-α-Aspartyl-, which is a mixture of N-L-α-aspartyl-L-phenylalanine 1-methyl and an organic acid having a co-amorphous structure. It also provides a method of masking the off-taste of L-phenylalanine 1-methyl.
　本発明は、さらに、
（２６）苦味を呈するアミノ酸と有機酸を含み、アミノ酸と有機酸がモル比１：１であり、アミノ酸と有機酸をボールミルで粉砕混合することを特徴とする、共非晶質構造を有する苦味を呈するアミノ酸と有機酸との混合物の製造方法
（２７）苦味を呈するアミノ酸と有機酸を含み、アミノ酸水溶液と有機酸水溶液をモル比１：１で混合し、１３０℃以上の温度で噴霧乾燥することを特徴とする、共非晶質構造を有する苦味を呈するアミノ酸と有機酸との混合物の製造方法
（２８）Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチル（Ａ）と有機酸（Ｂ）を含み、（Ａ）と（Ｂ）がモル比１：１であり、（Ａ）と（Ｂ）をボールミルで粉砕混合することを特徴とする、共非晶質構造を有する（Ａ）と（Ｂ）との混合物の製造方法
（２９）Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチル（Ａ）と有機酸（Ｂ）を含み、（Ａ）水溶液と（Ｂ）水溶液をモル比１：１となるように混合し、１３０℃以上の温度で噴霧乾燥することを特徴とする、共非晶質構造を有する（Ａ）と（Ｂ）との混合物の製造方法
をも提供するものである。 The present invention further
(26) A bitter taste having a co-amorphous structure, which comprises an amino acid and an organic acid exhibiting a bitter taste, the amino acid and the organic acid have a molar ratio of 1: 1 and the amino acid and the organic acid are pulverized and mixed by a ball mill. Method for producing a mixture of an amino acid exhibiting a bitter taste and an organic acid (27) A aqueous solution of an amino acid and an aqueous solution of an organic acid containing an amino acid and an organic acid exhibiting a bitter taste are mixed at a molar ratio of 1: 1 and spray-dried at a temperature of 130 ° C. or higher. A method for producing a mixture of a bitter-tasting amino acid having a co-amorphous structure and an organic acid (28) N-L-α-aspartyl-L-phenylalanine 1-methyl (A) and an organic acid (28). (A) has a co-amorphous structure, which comprises B), has a molar ratio of (A) and (B) of 1: 1, and is characterized by pulverizing and mixing (A) and (B) with a ball mill. (29) Method for producing a mixture of (B) and (B) N-L-α-aspartyl-L-phenylalanine 1-methyl (A) and an organic acid (B) are contained, and an aqueous solution (A) and an aqueous solution (B) are molarized. Also provided is a method for producing a mixture of (A) and (B) having a co-amorphous structure, which comprises mixing so as to have a ratio of 1: 1 and spray-drying at a temperature of 130 ° C. or higher. It is a thing.
　本発明において「異味」とは、通常の食品、医薬品を経口で摂取した際には感じられない不快な味および風味をいい、具体例としては苦み、渋み、辛み、えぐみ、ざらつき等が挙げられる。異味の有無や程度は、後述の実施例で示されるように官能評価によって評価できる。 In the present invention, the "unpleasant taste" refers to an unpleasant taste and flavor that cannot be felt when ordinary foods and pharmaceuticals are orally ingested, and specific examples thereof include bitterness, astringency, spiciness, harshness, and roughness. Be done. The presence or absence and degree of unpleasant taste can be evaluated by sensory evaluation as shown in Examples described later.
本発明で使用されるアミノ酸も有機酸も通常結晶として存在している。これらの単体の非晶質は不安定であり、放置しておくと結晶に転移してしまうからである。結晶は分子が規則正しく配列し、結晶格子を形成している。一方、非晶質は、結晶格子といった長距離秩序がなく、格子エネルギー等固体状態を安定化させる相互作用が非常に低いため、結晶に比べて安易に分散、水和し、溶解速度が速い。 Both the amino acids and organic acids used in the present invention usually exist as crystals. This is because the amorphous substances of these simple substances are unstable, and if left untreated, they will be transferred to crystals. Molecules are regularly arranged in a crystal to form a crystal lattice. On the other hand, amorphous does not have a long-range order such as a crystal lattice, and has a very low interaction for stabilizing a solid state such as lattice energy, so that it disperses and hydrates more easily than a crystal and has a faster dissolution rate.
　アミノ酸結晶は、ボールミルで磨砕すると高い衝撃力、剪断力が加わって非晶質化する。そして、その際、有機酸をカウンター物質として存在させると、有機酸はアミノ酸との親和性が高く、非晶質構造の状態を安定化させると考えられる。本発明の共非晶質構造体では、有機酸の親水性が高いため、通常のアミノ酸単体の非晶質構造体よりも水が入り込みやすく、さらに溶解速度や溶解量が向上していると考えられる。 Amino acid crystals are amorphized by applying high impact force and shearing force when crushed with a ball mill. At that time, if an organic acid is allowed to exist as a counter substance, it is considered that the organic acid has a high affinity with amino acids and stabilizes the state of the amorphous structure. In the co-amorphous structure of the present invention, since the hydrophilicity of the organic acid is high, it is considered that water can easily enter the co-amorphous structure of a normal amino acid alone, and the dissolution rate and the dissolution amount are further improved. Be done.
　ところで、本発明者は、先に特許出願（特願２０１９－１１７１３１号）したアミノ酸同士で形成される共非晶質構造体、例えば、チロシンとアルギニンの共非晶質構造体を水に溶解すると、図１１に模式的に示すように、共非晶質構造体になっているチロシンは、その速度論的溶解度が通常の結晶チロシンの熱力学的溶解度と比較して高く、チロシン濃度がかなり高いにもかかわらず、起晶せずに安定して溶解していることを見出した。 By the way, the present inventor dissolves a co-amorphous structure formed by amino acids of the earlier patent application (Japanese Patent Application No. 2019-117131), for example, a co-amorphous structure of tyrosine and arginine in water. As schematically shown in FIG. 11, tyrosine having a co-amorphous structure has a high kinetic solubility as compared with the thermodynamic solubility of ordinary crystalline tyrosine, and the tyrosine concentration is considerably high. Nevertheless, it was found that it was stably dissolved without crystallizing.
　図６には、シスチンとクエン酸が等モル含有した共非晶質構造体と、シスチンとクエン酸結晶を等モル混合した結晶混合物の上清シスチン濃度を比較した。共非晶質構造体は結晶混合物より高い溶解速度を持つ。本発明はいかなる理論にも拘束されるものではないが、共非晶質構造は結晶と比較して構造的に不安定であり、格子エネルギーが低いために、溶解しやすくなる。これは、医薬品業界では、結晶の溶解度はkinetic solubility（動力学的溶解度）、非晶質構造体の溶解度はthermodynamic solubility(熱力学的溶解度)と呼ばれ、一般的に認知されている。 FIG. 6 compares the supernatant cystine concentration of a co-amorphous structure containing an equimolar amount of cystine and citric acid and a crystal mixture obtained by an equimolar mixture of cystine and citric acid crystals. The co-amorphous structure has a higher dissolution rate than the crystalline mixture. Although the present invention is not bound by any theory, the co-amorphous structure is structurally unstable as compared with the crystal, and the lattice energy is low, so that the co-amorphous structure is easily dissolved. This is generally recognized in the pharmaceutical industry as the solubility of crystals is called kinetic solubility and the solubility of amorphous structures is called thermodynamic solubility.
　更に、図６で示されている共非晶質構造体が結晶より高い上清シスチン濃度で安定している理由は、共非晶質構造体は結晶として析出する際に、結晶と比較して析出に長い時間を要するためである。結晶は溶解すると結晶構造を保った会合体を水中で形成する一方、共非晶質構造体は結晶構造を持たないため、完全にランダムな会合体を水中で形成する。ランダム会合体から結晶構造をもった会合体に転移する必要があり、転移に長い時間を要する。 Furthermore, the reason why the co-amorphous structure shown in FIG. 6 is stable at a higher supernatant cystine concentration than the crystal is that the co-amorphous structure is more stable than the crystal when it is precipitated as a crystal. This is because it takes a long time to precipitate. When crystals dissolve, they form aggregates that retain their crystal structure in water, whereas co-amorphous structures do not have a crystal structure, so they form completely random aggregates in water. It is necessary to transfer from a random aggregate to an aggregate having a crystal structure, and the transition takes a long time.
　ところで、アミノ酸については、バリン、ロイシン、イソロイシンの３種のアミノ酸等の固溶体も知られており（ＷＯ２０１０／０５０１６８号公報）、この固溶体のバリン、ロイシン、イソロイシンは溶解速度が改善されることも知られている。しかしながら、固溶体は結晶格子の一部が他の分子で置換され、あるいは結晶格子間に他の分子が入り込んだものであり、つまり、結晶であって非晶質体のようなランダムな構造はしていない。固溶体の溶解速度は本発明の共非晶質構造体よりはるかに遅く、苦味等の改善効果も劣る。 By the way, as for amino acids, solid solutions of three kinds of amino acids such as valine, leucine and isoleucine are also known (WO2010 / 050168), and it is also known that the dissolution rates of these solid solutions of valine, leucine and isoleucine are improved. Has been done. However, a solid solution is one in which a part of the crystal lattice is replaced with another molecule or another molecule is inserted between the crystal lattices, that is, it is a crystal and has a random structure like an amorphous substance. Not. The dissolution rate of the solid solution is much slower than that of the co-amorphous structure of the present invention, and the effect of improving bitterness and the like is also inferior.
　本発明の共非晶質構造を有するアミノ酸含有化合物と有機酸の混合物は、アミノ基含有化合物の溶解速度を大幅に高めることができ、難溶性の化合物であっても容易に溶解できる。また、アミノ基含有化合物の苦味等をマスキングし、後味をなくし、あるいは口溶け感を良好にすることができる。 The mixture of the amino acid-containing compound having a co-amorphous structure and the organic acid of the present invention can significantly increase the dissolution rate of the amino group-containing compound, and even a poorly soluble compound can be easily dissolved. In addition, the bitterness and the like of the amino group-containing compound can be masked to eliminate the aftertaste or improve the melting feeling in the mouth.
実施例１で得られた各種アミノ酸とカウンター物質の混合物の粉末Ｘ線回析図である。FIG. 5 is a powder X-ray diffraction diagram of a mixture of various amino acids and a counter substance obtained in Example 1. Ｌｅｕ－クエン酸共非晶質体とＬｅｕ＋クエン酸結晶の溶解試験結果を示すグラフである。It is a graph which shows the dissolution test result of a Leu-citric acid co-amorphous substance and a Leu + citric acid crystal. Ｌｅｕ－Ａｒｇ共非晶質体とＬｅｕ＋Ａｒｇ結晶の溶解試験結果を示すグラフである。It is a graph which shows the dissolution test result of a Leu-Arg co-amorphous substance and a Leu + Arg crystal. Ｖａｌ－クエン酸共非晶質体とＶａｌ＋クエン酸結晶の溶解試験結果を示すグラフである。It is a graph which shows the dissolution test result of Val-citric acid co-amorphous substance and Val + citric acid crystal. Ｉｌｅ－クエン酸共非晶質体とＩｌｅ＋クエン酸結晶の溶解試験結果を示すグラフである。It is a graph which shows the dissolution test result of Ile-citric acid co-amorphous substance and Ile + citric acid crystal. Ｃｙｓ－クエン酸共非晶質体とＣｙｓ＋クエン酸結晶の溶解試験結果を示すグラフである。It is a graph which shows the dissolution test result of Cys-citric acid co-amorphous substance and Cys + citric acid crystal. Ｃｙｓ－クエン酸共非晶質体とＣｙｓ＋クエン酸結晶の溶解試験結果を示すグラフである。It is a graph which shows the dissolution test result of Cys-citric acid co-amorphous substance and Cys + citric acid crystal. 実施例３で得られたシスチンと各種有機酸の混合物の粉末Ｘ線回析図である。FIG. 5 is a powder X-ray diffraction diagram of a mixture of cystine and various organic acids obtained in Example 3. 実施例４で得られた各種アミノ酸とクエン酸の混合物の粉末Ｘ線回析図である。It is a powder X-ray diffraction diagram of the mixture of various amino acids and citric acid obtained in Example 4. 実施例５で得られたＮ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルと各種有機酸の混合物の粉末Ｘ線回析図である。FIG. 5 is a powder X-ray diffraction diagram of a mixture of N-L-α-aspartyl-L-phenylalanine 1-methyl and various organic acids obtained in Example 5. 結晶と非晶質の溶解挙動を模式的に説明するグラフである。It is a graph which schematically explains the dissolution behavior of a crystal and an amorphous.
　本発明の混合物は、アミノ基含有化合物と有機酸が非晶質構造になっているものである。 The mixture of the present invention has an amorphous structure of an amino group-containing compound and an organic acid.
　アミノ基含有化合物は、例えばアミノ酸、ペプチドなどである。 Amino group-containing compounds are, for example, amino acids and peptides.
　アミノ酸はＲ－ＣＨ（ＮＨ２）ＣＯＯＨで表わされ、Ｒは水素基、炭素数１～５のアルキル基、並びにヒドロキシル基、アミノ基、カルボキシル基、芳香環、スルフィド結合、ジスルフィド結合、チオール基及び／又は環状構造を含む基からなる群から選択された少なくとも１つの基を含むものである。 Amino acids are represented by R-CH (NH 2 ) COOH, where R is a hydrogen group, an alkyl group having 1 to 5 carbon atoms, a hydroxyl group, an amino group, a carboxyl group, an aromatic ring, a sulfide bond, a disulfide bond, and a thiol group. And / or those comprising at least one group selected from the group consisting of groups comprising a cyclic structure.
　Ｒが、水素基であるアミノ酸はグリシンであり、炭素数１～５のアルキル基であるアミノ酸は、アラニン、あるいはバリン、ロイシン、イソロイシン等の分岐鎖アミノ酸であっても良い。ヒドロキシル基を含むアミノ酸はセリン、スレオニン等であっても良く、アミノ基を含むアミノ酸は、リジン、アルギニン、オルニチン、グルタミン、アスパラギン等であっても良く、カルボキシル基を含むアミノ酸はアスパラギン酸、グルタミン酸等であっても良い。芳香環を含むアミノ酸はフェニルアラニン、チロシン等であっても良く、スルフィド又はジスルフィド結合を含むアミノ酸はメチオニン、シスチン等であっても良く、チオール基を含むアミノ酸はシステイン等であっても良い。環状構造を含むアミノ酸は、ヒスチジン、トリプトファン、プロリン、ヒドロキシプロリン等の複素環を含むものであっても良い。プロリン、ヒドロキシプロリンのようなイミノ酸も本発明のアミノ酸に含まれても良い。 The amino acid in which R is a hydrogen group is glycine, and the amino acid in which an alkyl group having 1 to 5 carbon atoms is an alkyl group may be alanine or a branched chain amino acid such as valine, leucine or isoleucine. The amino acid containing a hydroxyl group may be serine, threonine or the like, the amino acid containing an amino group may be lysine, arginine, ornithine, glutamine, aspartic acid or the like, and the amino acid containing a carboxyl group may be aspartic acid, glutamic acid or the like. It may be. The amino acid containing an aromatic ring may be phenylalanine, tyrosine or the like, the amino acid containing a sulfide or disulfide bond may be methionine, cystine or the like, and the amino acid containing a thiol group may be cysteine or the like. The amino acid containing a cyclic structure may contain a heterocycle such as histidine, tryptophan, proline, or hydroxyproline. Imino acids such as proline and hydroxyproline may also be included in the amino acids of the present invention.
　本発明の目的の一つは難溶性アミノ酸を容易に溶解できるようにすることである。難溶性アミノ酸には、シスチン、チロシン、トリプトファンなどの溶解度自体が低いものと、フェニルアラニン、バリン、ロイシン、イソロイシンのように溶解度自体はあるが、側鎖が疎水性であるため、水に投入しても水との親和性が低く、なかなか溶解できないものがあるため、本発明の共非晶質構造体はこれらのアミノ酸の溶解性を改良することである。 One of the objects of the present invention is to make it possible to easily dissolve a poorly soluble amino acid. Poorly soluble amino acids include those with low solubility such as cystine, tyrosine, and tryptophan, and those with solubility itself such as phenylalanine, valine, leucine, and isoleucine, but their side chains are hydrophobic, so they should be added to water. The co-amorphous structure of the present invention is to improve the solubility of these amino acids because some of them have low affinity with water and cannot be easily dissolved.
　またもう一つの目的は、これらの分岐鎖アミノ酸とフェニルアラニン、トリプトファン、アルギニン、チロシン、ヒスチジンなどは苦味を呈するアミノ酸としても知られており、シスチンなどは、口に入れると砂を噛む感触でざらつき感があることが知られていることから、本発明の共非晶質構造体はこれらの苦味やざらつき感をマスキングし、また、ざらつき感をなくして口溶け感を良好にすることである。 Another purpose is that these branched-chain amino acids and phenylalanine, tryptophan, arginine, tyrosine, histidine, etc. are also known as amino acids that exhibit a bitter taste, and cystine, etc., feels grainy when put in the mouth. Since it is known that the co-amino acid structure of the present invention masks these bitterness and graininess, and eliminates the graininess to improve the melting feeling in the mouth.
　ペプチドはアミノ酸がペプチド結合でつながったものであり、その結合数により、ジペプチド、トリペプチド等があるが、ペプチド、またはペプチド末端のカルボキシル基がメチルエステル等になったペプチドのエステル誘導体も有機酸との共非晶質構造体にすることができる。ペプチドの例としてはグリコマクロペプチド、ジロイシン、トリロイシンのような分岐鎖アミノ酸のペプチド類が挙げられる。例えば、ジペプチドであるＮ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチル（商標名「アスパルテーム」、略称 ＡＰ）は毒性のない甘味料として知られているが、甘味が残る後味がある。これを本発明の共非晶質構造体にすると、後味が軽減されて砂糖により近い味になることが分かった。 Peptides are amino acids linked by peptide bonds, and depending on the number of bonds, there are dipeptides, tripeptides, etc., but peptides or ester derivatives of peptides in which the carboxyl group at the end of the peptide is a methyl ester, etc. are also organic acids. Can be a co-amorphic structure. Examples of peptides include branched chain amino acid peptides such as glycomacropeptide, dileucine, and trileucine. For example, the dipeptide N-L-α-aspartame-L-phenylalanine 1-methyl (trade name "aspartame", abbreviated as AP) is known as a non-toxic sweetener, but has a residual sweetness. It was found that when this was made into the co-amorphous structure of the present invention, the aftertaste was reduced and the taste became closer to that of sugar.
　有機酸は、アミノ酸を除くカルボン酸の外、スルホン酸、フェノール等多種あるが、特にカルボン酸が望ましい。この有機酸はアミノ基含有化合物と共非晶質構造を形成するものである。カルボン酸の例としては、クエン酸、酒石酸、リンゴ酸、コハク酸、フタル酸、フマル酸などがある。有機酸は水和物であってもよく、また鉄塩、ナトリウム塩等の塩の形であってもよい。たとえば、クエン酸第一鉄ナトリウムであってよい。アミノ基含有化合物と有機酸の組合せは、両者で共非晶質構造を形成しうるものであればよい。 There are various kinds of organic acids such as sulfonic acid and phenol in addition to carboxylic acid excluding amino acids, but carboxylic acid is particularly desirable. This organic acid forms a co-amorphous structure with the amino group-containing compound. Examples of carboxylic acids include citric acid, tartaric acid, malic acid, succinic acid, phthalic acid, fumaric acid and the like. The organic acid may be a hydrate or may be in the form of a salt such as an iron salt or a sodium salt. For example, it may be sodium ferrous citrate. The combination of the amino group-containing compound and the organic acid may be any combination as long as it can form a co-amorphous structure.
　本発明の共非晶質構造との混合物におけるアミノ基含有化合物と有機酸の混合比は、共非晶質構造体を形成できればよく、例えば、モル比で１：０．１～１：１０でよく、好ましくは１：０．２～１：５であり、好ましくは１：０．５～１：２であり、さらに好ましくは１：０．６～１：２であり、さらに好ましくは６：４～４：６であり、もっとも好ましくはモル比で１：１が望ましい。通常はモル比で１：１でよいが、それに限らず共非晶質構造体を形成できればよい。例えばロイシンとクエン酸の場合は、モル比が６：４でもよい。 The mixing ratio of the amino group-containing compound and the organic acid in the mixture with the co-amorphous structure of the present invention may be as long as the co-amorphous structure can be formed, for example, in a molar ratio of 1: 0.1 to 1:10. It is often, preferably 1: 0.2 to 1: 5, preferably 1: 0.5 to 1: 2, more preferably 1: 0.6 to 1: 2, and even more preferably 6: It is 4 to 4: 6, and most preferably 1: 1 in molar ratio. Normally, the molar ratio may be 1: 1, but the molar ratio is not limited to this, as long as a co-amorphous structure can be formed. For example, in the case of leucine and citric acid, the molar ratio may be 6: 4.
　本発明のアミノ基含有化合物と有機酸は共非晶質構造になっているが、共非晶質構造とは、アミノ基含有化合物と有機酸が相互作用しあい、非晶質状態を保っている構造であり、両者が均一に分散、混合されている状態である。アミノ基含有化合物と有機酸を溶解して固化する方法、例えばスプレードライ法や、メルトクエンチング法（ホットメルト法）、凍結乾燥法を利用すれば、両者は溶液が固化した状態、つまり分子単位で混合している状態になり、粉体のまま混合して磨砕する方法、例えばボールミルで磨砕する方法を利用すれば両者は微粉となり、固体のまま分子単位で混合している状態になる。 The amino group-containing compound and the organic acid of the present invention have a co-amorphous structure, but in the co-amorphous structure, the amino group-containing compound and the organic acid interact with each other to maintain an amorphous state. It is a structure, and both are uniformly dispersed and mixed. If a method of dissolving and solidifying an amino group-containing compound and an organic acid, for example, a spray-drying method, a melt quenching method (hot melt method), or a freeze-drying method, both are in a solidified state of the solution, that is, a molecular unit. If you use the method of mixing and grinding the powder as it is, for example, the method of grinding with a ball mill, both will become fine powder and will be in a state of being mixed in molecular units as a solid. ..
　アミノ基含有化合物と有機酸が共非晶質構造になっているか否かは、公知の方法、例えばＸ線回折法、ラマン分光法などで確認することができる。 Whether or not the amino group-containing compound and the organic acid have a co-amorphous structure can be confirmed by a known method such as X-ray diffraction method or Raman spectroscopy.
　本発明の混合物は、アミノ基含有化合物と有機酸が共非晶質構造になっていれば足り、その他のアミノ基含有化合物、有機酸も含む３種以上の共非晶質構造になっていてもよい。また、アミノ基含有化合物、有機酸とは共非晶質構造になっていないその他のアミノ基含有化合物、有機酸、あるいは、共非晶質構造になっている、又はなっていないアミノ基含有化合物や有機酸以外の第三成分、それらの塩やその他の成分を含んでいてもよい。 The mixture of the present invention suffices if the amino group-containing compound and the organic acid have a co-amorphous structure, and has a co-amorphous structure of three or more kinds including other amino group-containing compounds and an organic acid. May be good. In addition, amino group-containing compounds, other amino group-containing compounds that do not have a co-amorphous structure with organic acids, organic acids, or amino group-containing compounds that have or do not have a co-amorphous structure. And third components other than organic acids, salts thereof and other components may be contained.
　本発明のアミノ基含有化合物や有機酸との共非晶質構造体は、アミノ基含有化合物、有機酸の非晶質体を製造する公知の方法、例えばボールミルを用いて磨砕する方法、例えばスプレードライヤーを用いる噴霧乾燥（噴霧造粒）法、メルトクエンチング法、凍結乾燥法などで製造できる。 The co-amorphous structure with an amino group-containing compound or an organic acid of the present invention is a known method for producing an amorphous body of an amino group-containing compound or an organic acid, for example, a method of grinding using a ball mill, for example. It can be produced by a spray drying (spray granulation) method using a spray dryer, a melt quenching method, a freeze drying method, or the like.
　ボールミルには、例えば、ヴァーダー・サイエンティフィック社製のボールミルＥｍａｘを使うことができる。このボールミルを用いる方法は、アミノ基含有化合物と有機酸を所定の混合比で投入し、必要により粉砕助剤を加えて共非晶質構造になるまで粉砕混合すればよい。投入するアミノ基含有化合物と有機酸は、結晶、非晶質のいずれでもよいが、通常は結晶である。粉砕助剤は、アミノ基含有化合物と有機酸の粉砕中の固結防止のために添加され、エタノール等をアミノ基含有化合物と有機酸の合計に対し、０．１～５質量％程度、好ましくは１～３質量％程度加えればよい。粉砕条件は、アミノ基含有化合物と有機酸が共非晶質構造になるまでであるが、通常、ボールミルの回転速度２００～１２００ｒｐｍで１～１２時間程度でよい。粉砕中、ボールミルの温度が上昇するので、ボールミルのポットを１５℃未満、好ましくは５～１５℃に冷却するのがよい。エタノール等の粉砕助剤は粉砕中に揮散して混合物には残らない。また、ボールミルには遊星ボールミル（（株）栗本鐵工所）、アトライター（日本コークス工業（株））、シモロイヤー（Ｚｏｚ　ＧｍｂＨ）をも使うことができる。 For the ball mill, for example, a ball mill Emax manufactured by Verder Scientific Co., Ltd. can be used. In the method using this ball mill, the amino group-containing compound and the organic acid may be added at a predetermined mixing ratio, and if necessary, a pulverizing aid may be added to pulverize and mix until a co-amorphous structure is formed. The amino group-containing compound and the organic acid to be added may be either crystalline or amorphous, but are usually crystalline. The pulverization aid is added to prevent solidification of the amino group-containing compound and the organic acid during pulverization, and ethanol or the like is preferably added in an amount of about 0.1 to 5% by mass based on the total amount of the amino group-containing compound and the organic acid. May be added in an amount of about 1 to 3% by mass. The pulverization conditions are until the amino group-containing compound and the organic acid have a co-amorphous structure, but usually, the rotation speed of the ball mill may be 200 to 1200 rpm for about 1 to 12 hours. Since the temperature of the ball mill rises during pulverization, it is preferable to cool the pot of the ball mill to less than 15 ° C, preferably 5 to 15 ° C. Grinding aids such as ethanol volatilize during milling and do not remain in the mixture. In addition, planetary ball mills (Kurimoto Iron Works Co., Ltd.), Atwriter (Nippon Coke Industries Co., Ltd.), and Simoroyer (Zoz GmbH) can also be used as ball mills.
　スプレードライによる製造の場合には、アミノ基含有化合物と有機酸を所定の混合比で含有する水溶液を調製し、１３０℃以上、好ましくは１６０℃以上の温度で噴霧乾燥する。 In the case of spray-drying, an aqueous solution containing an amino group-containing compound and an organic acid in a predetermined mixing ratio is prepared, and spray-dried at a temperature of 130 ° C. or higher, preferably 160 ° C. or higher.
　本発明のアミノ基含有化合物と有機酸の共非晶質構造体は、アミノ酸含有化合物の苦味、異味をマスキングする作用があるのでこれらのマスキング方法としても有用である。苦味を有するアミノ基含有化合物には、例えば、バリン、ロイシン、イソロイシン、フェニルアラニン、トリプトファン、アルギニン、チロシン、ヒスチジンなどのアミノ酸が挙げられる。 The co-amorphous structure of the amino group-containing compound and the organic acid of the present invention has an effect of masking the bitterness and unpleasant taste of the amino acid-containing compound, and is therefore useful as a masking method for these. Examples of the bittersweet amino group-containing compound include amino acids such as valine, leucine, isoleucine, phenylalanine, tryptophan, arginine, tyrosine, and histidine.
　また、シスチンは、口に入れたときに砂を噛む感触でざらつき感があるが、本発明の共非晶質構造にするとこのざらつき感がなくなり口どけが良好になるので、そのマスキング方法としても有用である。さらに、Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１メチル等は無害の甘味料として知られているが甘味が長く残る異味がある。しかし、これを本発明の共非晶質構造にすると甘味の消えるのが早くなり、異味感がなくなる。そこで、このようなジペプチドの甘味の異味感をなくすマスキング方法としても有用である。 In addition, cystine has a rough feel due to the feeling of biting sand when it is put in the mouth, but the co-amorphous structure of the present invention eliminates this rough feeling and improves the melting in the mouth, so it can also be used as a masking method. It is useful. Further, N-L-α-aspartyl-L-phenylalanine 1-methyl and the like are known as harmless sweeteners, but have a different taste in which the sweetness remains for a long time. However, when this is made into the co-amorphous structure of the present invention, the sweetness disappears quickly and the unpleasant sensation disappears. Therefore, it is also useful as a masking method for eliminating the unpleasant taste of sweetness of such dipeptides.
　本発明の用途はいかなる制限もされないが、アミノ基含有化合物と有機酸とが共非晶質構造になっている混合物は、新たな用途に用いることもできるし、従来使用されているアミノ基含有化合物や無機化合物あるいは有機酸に代替することができる。この用途としては、各種飲料、甘味料、調味料、飲料用粉末、健康食品、経口医薬品、培地などを挙げることができる。可食性製品は、経口摂取される組成物又は口腔内に使用される組成物であって、食品、調味料、医薬品、医薬部外品、香粧品が包含され、可食性粉末製品は、これらを粉末にしたものであり、例えば粉末を水に溶かして飲料にする製品（スポーツドリンク用粉末）等である。 The uses of the present invention are not limited in any way, but a mixture of an amino group-containing compound and an organic acid having a co-amorphous structure can be used for new uses or contains conventionally used amino groups. It can be replaced with a compound, an inorganic compound or an organic acid. Examples of this application include various beverages, sweeteners, seasonings, beverage powders, health foods, oral medicines, media and the like. Edible products are compositions that are taken orally or used in the oral cavity, and include foods, seasonings, pharmaceuticals, non-pharmaceutical products, and cosmetics, and edible powder products include these. It is a powder, for example, a product (powder for sports drinks) in which the powder is dissolved in water to make a beverage.
　実施例１
（１）アミノ酸・カウンター共非晶質混合物の作製
　ロイシン（Ｌｅｕ）（味の素社製）４．０６ｇ（０．０３１ｍｏｌ）、クエン酸（富士フィルムワコーケミカル株式会社製）５．９４ｇ（０．０３１ｍｏｌ）と粉砕助剤としてエタノール０．４ｍＬをジルコニア製の１２５ｍＬのポットに入れた。ポットにジルコニア製の１０ｍｍボール５０個を入れ、ボールミル(ヴァーダー・サイエンティフィック社製、レッチェ Ｅｍａｘ)にセットした。回転数１０００ｒｐｍ、その間、ポットの外周に１５℃の冷却水を流して粉砕温度約２８℃で６時間粉砕混合を行い、粉体９．１ｇを得た。 Example 1
(1) Preparation of Amino Acid / Counter Co-Amorphous Mixture Leucine (manufactured by Ajinomoto Co., Inc.) 4.06 g (0.031 mol), citric acid (manufactured by Fuji Film Wako Chemical Co., Ltd.) 5.94 g (0.031 mol) And 0.4 mL of ethanol as a pulverizing aid was placed in a 125 mL pot made of zirconia. 50 zirconia 10 mm balls were placed in a pot and set in a ball mill (Vader Scientific, Lecce Emax). A cooling water of 15 ° C. was flowed around the outer periphery of the pot at a rotation speed of 1000 rpm, and pulverization and mixing were carried out at a pulverization temperature of about 28 ° C. for 6 hours to obtain 9.1 g of powder.
　アミノ酸とカウンター物質を表１の２番目以降に変えて同様に非晶質混合物の作製を行い、混合物の粉体を得た。 Amino acids and counter substances were changed to the second and subsequent substances in Table 1 to prepare an amorphous mixture in the same manner, and a powder of the mixture was obtained.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　尚、今回は６時間で統一しているが、もっと短時間で共非晶質化するものもある。例えば、Ｌｅｕ－クエン酸は１０分程度でも共非晶質化する。 In addition, although it is unified in 6 hours this time, there are some that co-amorphize in a shorter time. For example, Leu-citric acid co-amorphizes even in about 10 minutes.
（２）非晶質化の確認実験
　（１）で得られた固体を粉末Ｘ線回折装置（Ｍａｌｖｅｒｎ　Ｐａｎａｌｙｔｉｃａｌ社製、Ｅｍｐｙｒｅａｎ）を用いて該固体の粉末Ｘ線回折パターンを得た。得られた結果を図１に示す。その結果、Ｌｅｕ－クエン酸、Ｌｅｕ－酒石酸、Ｌｅｕ－Ａｒｇ、（Ｖａｌ－クエン酸、Ｉｌｅ－クエン酸）Ｖａｌ－Ａｒｇ、Ｉｌｅ－Ａｒｇについては結晶構造に特有の明確なピークは確認されなかった。このことから、（１）で得られたＬｅｕ－クエン酸、Ｌｅｕ－酒石酸、Ｌｅｕ－Ａｒｇ、（Ｖａｌ－クエン酸、Ｉｌｅ－クエン酸）Ｖａｌ－Ａｒｇ、Ｉｌｅ－Ａｒｇの固体は非晶質であることが確認できた。一方、Ｌｅｕ－リンゴ酸、Ｌｅｕ－Ｇｌｙ、Ｌｅｕ－Ａｌａ、Ｌｅｕ－Ｓｅｒについては結晶構造に特有の明確なピークが確認された。 (2) Confirmation Experiment of Amorphization The solid obtained in (1) was used to obtain a powder X-ray diffraction pattern of the solid using a powder X-ray diffractometer (Empylean, manufactured by Malvern Panasonic). The obtained results are shown in FIG. As a result, no clear peak peculiar to the crystal structure was confirmed for Leu-citric acid, Leu-tartaric acid, Leu-Arg, (Val-citric acid, Ile-citric acid) Val-Arg, and Ile-Arg. From this, the solids of Leu-citric acid, Leu-tartaric acid, Leu-Arg, (Val-citric acid, Ile-citric acid) Val-Arg, and Ile-Arg obtained in (1) are amorphous. I was able to confirm that. On the other hand, for Leu-malic acid, Leu-Gly, Leu-Ala, and Leu-Ser, clear peaks peculiar to the crystal structure were confirmed.
（３）溶解量確認試験
　ポリプロピレン製２００ｍＬサンプル瓶に、それぞれ１ｍｏｌ／Ｌ－トリス－塩酸緩衝液(ｐＨ７．６)１００ｍＬと、（１）で得られた固体を２．４６ｇと、別のサンプル瓶に予めボールミル(ヴァーダー・サイエンティフィック社製、レッチェ Ｅｍａｘ)で１分間粉砕したＬｅｕ結晶１ｇとクエン酸結晶１．４６ｇを入れ、それぞれ２５℃のウォーターバス（東京理化器械社製 ＮＣＢ－３３００）に浸け、マグネチックスターラー（アズワン株式会社製　Ｂ－１マグネチックスターラーオクトパス）を用いて撹拌した。１分経過後、それぞれのサンプル瓶から２ｍＬサンプリングし、０．４５μｍフィルター（ジーエルサイエンス社 クロマトディスク）を用いて濾過した。濾過したサンプルを２００倍希釈して高速液体クロマトグラフィー（ＨＰＬＣ）（Ａｇｉｌｅｎｔ社製 １１００ Ｓｅｒｉｅｓ）を用いて上清のＬｅｕ濃度を定量した。 (3) Dissolution confirmation test In a 200 mL sample bottle made of polypropylene, 100 mL of 1 mol / L-Tris-hydrochloric acid buffer (pH 7.6) and 2.46 g of the solid obtained in (1) are added to another sample bottle. 1 g of Leu crystals and 1.46 g of citric acid crystals crushed in advance with a ball mill (Letche Emax, manufactured by Verder Scientific) for 1 minute are placed in a water bath (NCB-3300, manufactured by Tokyo Rika Kikai Co., Ltd.) at 25 ° C. It was soaked and stirred using a magnetic stirrer (B-1 magnetic stirrer Octopus manufactured by AS ONE Co., Ltd.). After 1 minute, 2 mL was sampled from each sample bottle and filtered using a 0.45 μm filter (GL Sciences chromatodisc). The filtered sample was diluted 200-fold and the Leu concentration of the supernatant was quantified using high performance liquid chromatography (HPLC) (1100 Series, manufactured by Agilent).
　３分、５分、１０分、２０分経過した後も同様の操作を行った。得られた結果を図２に示す。このことから、（１）で得られたＬｅｕ－クエン酸の固体は、粉砕した結晶と比較して溶解が速いことが確認できた。 The same operation was performed after 3 minutes, 5 minutes, 10 minutes, and 20 minutes had passed. The obtained results are shown in FIG. From this, it was confirmed that the solid Leu-citric acid obtained in (1) dissolves faster than the crushed crystals.
　アミノ酸とカウンター物質を表２の２番目以降に変えて同様に溶解量確認試験を行ない、図３～図５に示す結果を得た。このことから、（１）で得られた、Ｌｅｕ－Ａｒｇ、Ｖａｌ－クエン酸、Ｉｌｅ－クエン酸の固体は、粉砕した結晶と比較して溶解が速いことが確認できた。 The amino acids and counter substances were changed to the second and subsequent substances in Table 2, and the dissolution amount confirmation test was conducted in the same manner, and the results shown in FIGS. 3 to 5 were obtained. From this, it was confirmed that the solids of Leu-Arg, Val-citric acid, and Ile-citric acid obtained in (1) dissolve faster than the crushed crystals.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
（４）官能試験結果
　（１）で作成したＬｅｕ－クエン酸のコアモルファスについて苦みのマスキング能力の官能試験を行った。 (4) Sensory test results A sensory test of bitterness masking ability was performed on the co-amorphous Leu-citric acid prepared in (1).
　パネラーは３０名で、Ｌｅｕ－クエン酸のコアモルファスと結晶混合物の２種類の苦みを５段階（すごく感じた（５）、感じた（４）、少し感じた（３）、あまり感じなかった（２）、ほとんど感じなかった（１））で評価した。 There were 30 panelists, and they felt two kinds of bitterness of Leu-citric acid co-amorphous and crystalline mixture in five stages (very felt (5), felt (4), felt a little (3), and did not feel much (3). 2), I hardly felt it (1)).
　評価の結果を表３に示した。その結果、コアモルファスは結晶混合物と比較して苦みを感じないと評価された。 The evaluation results are shown in Table 3. As a result, co-amorphous was evaluated to be less bitter than the crystal mixture.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　実施例２
　シスチン（Ｃｙｓ２）（味の素社製）５．５６ｇ（０．０２７ｍｏｌ）、クエン酸（富士フイルムワコーケミカル株式会社製）４．４４ｇ（０．０２７ｍｏｌ）と粉砕助剤としてエタノール０．２ｍｌを用い、実施例１の（１）と同様に粉砕混合を行い、粉体９．７ｇを得た。 Example 2
Conducted using cystine (Cys2) (manufactured by Ajinomoto Co., Inc.) 5.56 g (0.027 mol), citric acid (manufactured by Fujifilm Wako Chemical Co., Ltd.) 4.44 g (0.027 mol) and 0.2 ml of ethanol as a pulverizing aid. The same pulverization and mixing as in (1) of Example 1 was carried out to obtain 9.7 g of powder.
　この固体を実施例１の（３）と同様にして溶解量確認試験を行なった。得られた結果を図６および図７に示す。 This solid was subjected to a dissolution amount confirmation test in the same manner as in (3) of Example 1. The obtained results are shown in FIGS. 6 and 7.
実施例３
　シスチン（Ｃｙｓ２）（味の素社製）と、表４に示す有機酸と粉砕助剤としてエタノール０．２ｍｌを用い、実施例１の（１）と同様に粉砕混合を行い、粉体を得た。
　この固体を実施例１の（２）と同様にして粉末X線回折パターンを得た。得られた結果を図８に示す。いずれの粉体も結晶に特有の明確なピークは認められず非晶質の粉体であることが確認された。
Figure JPOXMLDOC01-appb-T000004
 Example 3
Using cystine (Cys2) (manufactured by Ajinomoto Co., Inc.), the organic acid shown in Table 4, and 0.2 ml of ethanol as a pulverizing aid, pulverization and mixing were carried out in the same manner as in (1) of Example 1 to obtain a powder.
This solid was used in the same manner as in (2) of Example 1 to obtain a powder X-ray diffraction pattern. The obtained results are shown in FIG. It was confirmed that none of the powders had a clear peak peculiar to crystals and was an amorphous powder.
Figure JPOXMLDOC01-appb-T000004
実施例４
アミノ酸（味の素社製）と、表５に示す有機酸と粉砕助剤としてエタノール０．２ｍｌを用い、実施例１の（１）と同様に粉砕混合を行い、粉体を得た。
　この固体を実施例１の（２）と同様にして粉末X線回折パターンを得た。得られた結果を図９に示す。いずれの粉体も結晶に特有の明確なピークは認められず非晶質の粉体であることが確認された。
Figure JPOXMLDOC01-appb-T000005
 Example 4
Amino acids (manufactured by Ajinomoto Co., Inc.), organic acids shown in Table 5, and 0.2 ml of ethanol as a pulverizing aid were used and pulverized and mixed in the same manner as in (1) of Example 1 to obtain a powder.
This solid was used in the same manner as in (2) of Example 1 to obtain a powder X-ray diffraction pattern. The obtained results are shown in FIG. It was confirmed that none of the powders had a clear peak peculiar to crystals and was an amorphous powder.
Figure JPOXMLDOC01-appb-T000005
実施例５
Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチル（商標名「アスパルテーム」ＡＰ）味の素社製）と、表６に示す有機酸と粉砕助剤としてエタノール０．２ｍｌを用い、実施例１の（１）と同様に粉砕混合を行い、粉体を得た。
　この固体を実施例１の（２）と同様にして粉末X線回折パターンを得た。得られた結果を図１０に示す。フマル酸とクエン酸をＡＰと混合した粉体は結晶に特有の明確なピークは認められず非晶質の粉体であることが確認された。また、ＡＰとクエン酸とを粉砕混合した粉体は、異味がマスキングされて後味がほとんどなくクエン酸のおかげで爽やかな甘味を呈した。一方で、ＡＰとリンゴ酸、酒石酸、コハク酸とを粉砕混合した粉体は非晶質であるとは認められなかった。
Figure JPOXMLDOC01-appb-T000006
 Example 5
Example 1 using N-L-α-aspartame-L-phenylalanine 1-methyl (trade name "aspartame" AP) manufactured by Ajinomoto Co., Inc.), the organic acid shown in Table 6, and 0.2 ml of ethanol as a pulverizing aid. The powder was obtained by pulverizing and mixing in the same manner as in (1).
This solid was used in the same manner as in (2) of Example 1 to obtain a powder X-ray diffraction pattern. The obtained results are shown in FIG. It was confirmed that the powder obtained by mixing fumaric acid and citric acid with AP was an amorphous powder without a clear peak peculiar to crystals. In addition, the powder obtained by pulverizing and mixing AP and citric acid exhibited a refreshing sweetness thanks to citric acid, with the off-flavor masked and almost no aftertaste. On the other hand, the powder obtained by pulverizing and mixing AP with malic acid, tartaric acid, and succinic acid was not found to be amorphous.
Figure JPOXMLDOC01-appb-T000006
実施例６　スプレードライによる製造
　ロイシン４．００ｇとクエン酸５．８５ｇを水１２０ｇに溶解させて、１７０℃の温度で噴霧乾燥するとロイシンとクエン酸の共非晶質が４．２ｇ得られた。 Example 6 Production by spray drying When 4.00 g of leucine and 5.85 g of citric acid were dissolved in 120 g of water and spray-dried at a temperature of 170 ° C., 4.2 g of co-amorphous of leucine and citric acid was obtained.
　本発明の共非晶質構造体は、その構成成分であるアミノ酸やペプチドなどのアミノ基含有化合物の溶解性が良好であるばかりでなく、苦味や異味などのマスキング効果もあり、アミノ基含有化合物を飲料、調味料、甘味料などを含む食品分野あるいは医薬品分野などで幅広く利用でき、特に難溶性アミノ酸の溶解を含む用途や、苦味を呈するアミノ酸、また、甘味が長く残るペプチドへの利用に有効である。 The co-amorphous structure of the present invention not only has good solubility of amino group-containing compounds such as amino acids and peptides, which are constituents thereof, but also has a masking effect such as bitterness and off-taste, and is an amino group-containing compound. Can be widely used in the food field including beverages, seasonings, sweeteners, etc. or in the pharmaceutical field, and is particularly effective for applications including dissolution of sparingly soluble amino acids, amino acids that exhibit a bitter taste, and peptides that have a long-lasting sweetness. Is.

Claims (30)

  1. 　アミノ基含有化合物と有機酸とが共非晶質構造になっていることを特徴とする、アミノ基含有化合物と有機酸の混合物。 A mixture of an amino group-containing compound and an organic acid, characterized in that the amino group-containing compound and the organic acid have a co-amorphous structure.
  2. 　アミノ基含有化合物が、ペプチドまたはアミノ酸であることを特徴とする請求項１に記載の混合物。 The mixture according to claim 1, wherein the amino group-containing compound is a peptide or an amino acid.
  3. 　アミノ基含有化合物が、ロイシン、イソロイシン、バリン、シスチン、フェニルアラニン、チロシン、トリプトファン、アルギニン、ヒスチジンからなる群から少なくとも一つ選択されるアミノ酸であることを特徴とする請求項２に記載の混合物。 The mixture according to claim 2, wherein the amino group-containing compound is an amino acid selected at least from the group consisting of leucine, isoleucine, valine, cystine, phenylalanine, tyrosine, tryptophan, arginine, and histidine.
  4. 　アミノ基含有化合物がアミノ酸であり、該アミノ酸が分岐鎖アミノ酸であることを特徴とする請求項２に記載の混合物。 The mixture according to claim 2, wherein the amino group-containing compound is an amino acid, and the amino acid is a branched-chain amino acid.
  5. 　分岐鎖アミノ酸が、ロイシン、イソロイシンまたはバリンであることを特徴とする請求項４に記載の混合物。 The mixture according to claim 4, wherein the branched chain amino acid is leucine, isoleucine or valine.
  6. 　アミノ基含有化合物がアミノ酸であり、該アミノ酸が、苦味を呈するアミノ酸であることを特徴とする請求項２に記載の混合物。 The mixture according to claim 2, wherein the amino group-containing compound is an amino acid, and the amino acid is an amino acid exhibiting a bitter taste.
  7. 　アミノ基含有化合物がペプチドであり、該ペプチドがジペプチドであることを特徴とする請求項２に記載の混合物。 The mixture according to claim 2, wherein the amino group-containing compound is a peptide, and the peptide is a dipeptide.
  8. 　ペプチドがＮ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルであることを特徴とする請求項２に記載の混合物。 The mixture according to claim 2, wherein the peptide is N-L-α-aspartyl-L-phenylalanine 1-methyl.
  9. 　有機酸が、クエン酸、酒石酸、リンゴ酸、フタル酸、フマル酸もしくはコハク酸または、それぞれの塩もしくは水和物であることを特徴とする請求項１または２に記載の混合物。 The mixture according to claim 1 or 2, wherein the organic acid is citric acid, tartaric acid, malic acid, phthalic acid, fumaric acid or succinic acid, or salts or hydrates thereof.
  10. 　有機酸がクエン酸第一鉄またはその塩であることを特徴とする請求項９に記載の混合物。 The mixture according to claim 9, wherein the organic acid is ferrous citrate or a salt thereof.
  11. 　アミノ基含有化合物がロイシン、イソロイシンまたはバリンであるアミノ酸であり、有機酸がクエン酸、酒石酸またはリンゴ酸であることを特徴とする請求項２に記載の混合物。 The mixture according to claim 2, wherein the amino group-containing compound is an amino acid such as leucine, isoleucine or valine, and the organic acid is citric acid, tartaric acid or malic acid.
  12. 　アミノ酸がロイシンであり、有機酸がクエン酸であることを特徴とする請求項１１に記載の混合物。 The mixture according to claim 11, wherein the amino acid is leucine and the organic acid is citric acid.
  13. 　アミノ酸がチロシンであることを特徴とする請求項１０に記載の混合物。 The mixture according to claim 10, wherein the amino acid is tyrosine.
  14. アミノ酸がシスチンであることを特徴とする請求項１０に記載の混合物。 The mixture according to claim 10, wherein the amino acid is cystine.
  15. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする飲料。 A beverage comprising the mixture according to any one of claims 1 to 13.
  16. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする調味料。 A seasoning comprising the mixture according to any one of claims 1 to 13.
  17. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする甘味料。 A sweetening agent comprising the mixture according to any one of claims 1 to 13.
  18. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする培地。 A medium comprising the mixture according to any one of claims 1 to 13.
  19. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする経口医薬品。 An oral drug comprising the mixture according to any one of claims 1 to 13.
  20. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする苦味および／または異味をマスキングされた可食性製品。 An edible product masked with bitterness and / or off-taste, which comprises the mixture according to any one of claims 1 to 13.
  21. 　請求項１～１３のいずれかに記載の混合物を含むことを特徴とする苦味および／または異味をマスキングされた可食性粉末製品。 An edible powder product masked with bitterness and / or off-taste, which comprises the mixture according to any one of claims 1 to 13.
  22. 　苦みを呈するアミノ酸と有機酸がモル比４：６～６：４で含まれる混合物が共非晶質構造になっていることを特徴とするアミノ酸の苦味をマスキングする可食性製品。 An edible product that masks the bitterness of amino acids, which is characterized by having a co-amorphous structure in a mixture containing bitter amino acids and organic acids in a molar ratio of 4: 6 to 6: 4.
  23. 　アミノ酸と有機酸がモル比１：１である請求項２２に記載の可食性製品。 The edible product according to claim 22, wherein the amino acid and the organic acid have a molar ratio of 1: 1.
  24. 　Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルと有機酸がモル比１：１で含まれる混合物が共非晶質構造になっていることを特徴とする、Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルの異味をマスキングする可食性製品。 NL-α-aspartyl is characterized in that a mixture containing N-L-α-aspartyl-L-phenylalanine 1-methyl and an organic acid in a molar ratio of 1: 1 has a co-amorphous structure. -An edible product that masks the off-taste of L-Phenylalanine 1-methyl.
  25. 苦みを呈するアミノ酸と有機酸が共非晶質構造になっている混合物であることを特徴とするアミノ酸の苦味をマスキングする方法。 A method for masking the bitter taste of an amino acid, which is a mixture of a bitter amino acid and an organic acid having a co-amorphous structure.
  26. 　Ｎ－Ｌ－α-アスパルチル－Ｌ－フェニルアラニン１－メチルと有機酸が共非晶質構造になっている混合物であることを特徴とする、Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチルの異味をマスキングする方法。 N-L-α-aspartyl-L-phenylalanine 1-methyl, which is a mixture of N-L-α-aspartyl-L-phenylalanine 1-methyl and an organic acid having a co-amorphous structure. How to mask the strange taste of.
  27. 　苦味を呈するアミノ酸と有機酸を含み、アミノ酸と有機酸がモル比１：１であり、アミノ酸と有機酸をボールミルで粉砕混合することを特徴とする、共非晶質構造を有する苦味を呈するアミノ酸と有機酸との混合物の製造方法。 An amino acid having a co-amorphous structure, which contains a bitter-tasting amino acid and an organic acid, has a molar ratio of the amino acid to the organic acid of 1: 1 and is characterized by pulverizing and mixing the amino acid and the organic acid with a ball mill. A method for producing a mixture of an organic acid and an organic acid.
  28. 　苦味を呈するアミノ酸と有機酸を含み、アミノ酸水溶液と有機酸水溶液をモル比１：１で混合し、１３０℃以上の温度で噴霧乾燥することを特徴とする、共非晶質構造を有する苦味を呈するアミノ酸と有機酸との混合物の製造方法。 A bitter taste having a co-amorphous structure, which contains an amino acid and an organic acid exhibiting a bitter taste, is characterized by mixing an aqueous amino acid solution and an aqueous organic acid solution at a molar ratio of 1: 1 and spray-drying at a temperature of 130 ° C. or higher. A method for producing a mixture of an amino acid and an organic acid.
  29. 　Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチル（Ａ）と有機酸（Ｂ）を含み、（Ａ）と（Ｂ）がモル比１：１であり、（Ａ）と（Ｂ）をボールミルで粉砕混合することを特徴とする、共非晶質構造を有する（Ａ）と（Ｂ）との混合物の製造方法。 It contains N-L-α-aspartyl-L-phenylalanine 1-methyl (A) and an organic acid (B), (A) and (B) have a molar ratio of 1: 1 and (A) and (B). A method for producing a mixture of (A) and (B) having a co-amorphous structure, which comprises pulverizing and mixing with a ball mill.
  30. 　Ｎ－Ｌ－α－アスパルチル－Ｌ－フェニルアラニン１－メチル（Ａ）と有機酸（Ｂ）を含み、（Ａ）水溶液と（Ｂ）水溶液をモル比１：１となるように混合し、１３０℃以上の温度で噴霧乾燥することを特徴とする、共非晶質構造を有する（Ａ）と（Ｂ）との混合物の製造方法。 It contains N-L-α-aspartyl-L-phenylalanine 1-methyl (A) and an organic acid (B), and the aqueous solution (A) and the aqueous solution (B) are mixed so as to have a molar ratio of 1: 1 at 130 ° C. A method for producing a mixture of (A) and (B) having a co-amorphous structure, which comprises spray-drying at the above temperature.
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