JP7778626B2 - Hydroxyalkanoate Composition - Google Patents

Description

The present invention relates to a hydroxyalkanoate composition.

Hydroxyalkanoic acids, such as 3-hydroxybutyric acid (hereinafter simply referred to as "3HB"), are substances that are naturally present in the human body and are attracting attention as a revolutionary energy source that can replace carbohydrates.

When ingested, hydroxyalkanoic acids such as 3HB are metabolized in the body via medium-chain fatty acids (MCTs) found in coconut oil, for example, and then transported to the bloodstream where they are converted into energy. This process allows for faster conversion to energy than carbohydrates that go through the glycolytic pathway. In other words, when ingested externally, hydroxyalkanoic acids such as 3HB are converted into energy more quickly than carbohydrates that go through the glycolytic pathway.

Furthermore, hydroxyalkanoic acids such as 3HB have the effect of inhibiting the absorption of fat and sugar by cells. In other words, ingesting hydroxyalkanoic acids such as 3HB from an external source has the effect of inhibiting sugar absorption and promoting fat burning, resulting in a diet.

In addition, hydroxyalkanoic acids such as 3HB not only serve as an energy source, but have also been shown to improve cognitive function and long-term memory function, as well as be effective in preventing Alzheimer's disease.

In light of the functions of hydroxyalkanoic acids such as 3HB, their use as energy substances for athletes or as diet and health foods is being considered.

Hydroxyalkanoic acids such as 3HB are highly hygroscopic, making them difficult to handle in their original state. Furthermore, their strong sour taste makes them unpleasant to ingest orally. To improve the handleability of hydroxyalkanoic acids, it is conceivable to add anti-caking agents such as silicon dioxide, calcium silicate, or dextrin. However, these ingredients have upper intake limits and contain carbohydrates, making them undesirable in combination with hydroxyalkanoic acids such as 3HB. For this reason, hydroxyalkanoic acids such as 3HB are generally provided as powders in the form of neutralized salts. Patent Document 1 cites examples of neutralized salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, which are minerals with a high tolerance for intake by the human body.

U.S. Pat. No. 1,073,6861

However, there are concerns about excessive intake of the neutralized salt mentioned above, or what is known as excessive salt intake. Among minerals, sodium and potassium have a high tolerance for intake, but sodium is often ingested as table salt in a normal diet, so there are restrictions on its intake outside of meals.

For this reason, in order to increase the intake of hydroxyalkanoic acids such as 3HB, it is necessary to ingest them in the form of potassium salts. However, potassium salts are compounds that exhibit extremely high hygroscopicity, with the water vapor adsorption isotherm showing a significant increase in the amount of water vapor adsorbed in low-humidity environments of approximately 35% relative humidity. For this reason, potassium salts are difficult to manufacture, and are currently rarely available in the market.

The sodium salt is also a compound whose water vapor adsorption capacity increases significantly in an environment with a relative humidity of approximately 45%, demonstrating hygroscopicity. Because its hygroscopicity is not as high as that of the potassium salt, it is difficult to manufacture in high-humidity environments and is not suitable for storage, although it is available on the market.

For these reasons, there is a need to reduce the hygroscopicity of hydroxyalkanoate compositions containing 3HB potassium salt, etc. Therefore, the main object of the present invention is to provide a hydroxyalkanoate composition with low hygroscopicity.

As a result of extensive research to achieve the above-mentioned objective, the inventors discovered that when a hydroxyalkanoic acid is a mixed salt of an alkali metal salt and an alkaline earth metal salt, and the contents of the alkali metal salt and alkaline earth metal salt are set within a predetermined range, the crystallinity of the hydroxyalkanoic acid salt composition can be reduced by, for example, drying, thereby making it amorphous, and ultimately reducing its hygroscopicity, thereby completing the present invention. Specifically, the present invention encompasses the following features.

Item 1. A hydroxyalkanoate composition containing an alkali metal hydroxyalkanoate and an alkaline earth metal hydroxyalkanoate,
the content of the alkali metal hydroxyalkanoate salt is 1 to 70 mol % in terms of the amount of alkali metal, with the total amount of the alkali metal and alkaline earth metal being 100 mol %,
The content of the alkaline earth metal salt of hydroxyalkanoic acid is 30 to 99 mol % in terms of the amount of alkaline earth metal, and
is amorphous,
Hydroxyalkanoate compositions.

Item 2. The hydroxyalkanoate composition according to Item 1, wherein the alkali metal hydroxyalkanoate is at least one selected from the group consisting of sodium salts, potassium salts, and lithium salts of hydroxyalkanoic acid.

Item 3. The hydroxyalkanoate composition according to Item 1 or 2, wherein the alkaline earth metal hydroxyalkanoate is at least one selected from the group consisting of magnesium salts, calcium salts, and barium salts of hydroxyalkanoic acid.

Item 4. The hydroxyalkanoate composition according to any one of Items 1 to 3, wherein the hydroxyalkanoic acid is 3-hydroxybutyric acid.

Item 5. The hydroxyalkanoate composition according to any one of Items 1 to 4, wherein, in an X-ray diffraction pattern using CuKα radiation, there is no peak at a diffraction angle 2θ = 6.38° with a full width at half maximum of 0.50° or less, or there are no peaks at diffraction angles 2θ = 6.70° and 7.08° with a full width at half maximum of 0.50° or less, within a tolerance of ±0.5°, or there is only a halo.

Item 6. The hydroxyalkanoate composition according to any one of Items 1 to 5, wherein the alkali metal hydroxyalkanoate and alkaline earth metal hydroxyalkanoate contain an R configuration.

Item 7. The hydroxyalkanoate composition according to any one of Items 1 to 6, which is an orally ingested hydroxyalkanoate composition.

Item 8. A dietary supplement containing the hydroxyalkanoate composition described in any one of Items 1 to 7.

Item 9. A method for producing the hydroxyalkanoate composition according to any one of Items 1 to 7 or the dietary supplement according to Item 8, comprising:
The method comprises the step of mixing a hydroxyalkanoic acid with an alkali metal and an alkaline earth metal in a solution,
the mixed solution is adjusted so that the content of the alkali metal in the mixed solution is 1 to 70 mol % and the content of the alkaline earth metal salt in the mixed solution is 30 to 99 mol %, where the total amount of the alkali metal and alkaline earth metal is 100 mol %.

Item 10. The manufacturing method described in Item 9, wherein the solvent constituting the solution is a polar solvent.

Item 11. The manufacturing method described in Item 9 or 10, wherein the solvent constituting the solution is water.

Item 12. After the mixing,
Item 12. The method according to any one of Items 9 to 11, further comprising concentrating and/or drying the resulting mixture.

Item 13. The manufacturing method described in Item 12, wherein the drying is carried out by spray drying to form a dry powder.

The present invention makes it possible to provide a hydroxyalkanoate composition in which the hygroscopicity of alkali metal salts of hydroxyalkanoic acids such as 3HB is further reduced.

In particular, the present invention makes it possible to produce potassium-containing salts, which have been extremely difficult to produce, by incorporating alkaline earth metal salts. It also makes it possible to obtain amorphous hydroxyalkanoate compositions with specific compositions, and these compositions have reduced hygroscopicity.

1 shows the results of the moisture absorption test in Test Example 1 for the powders obtained in Examples 1 and 2 and Comparative Examples 1 to 5. 1 shows the results of the moisture absorption test in Test Example 2 for the powders obtained in Examples 2 to 5 and Comparative Examples 1, 3 and 6. 1 shows the results of moisture vapor absorption isotherms of Test Example 3 for the powders obtained in Examples 1 and 2 and Comparative Example 1. 1 shows the results of moisture vapor absorption isotherms of Test Example 3 for the powders obtained in Examples 6 and 7 and Comparative Examples 4 and 5.

In this specification, the term "containing" is a concept that encompasses all of "comprise," "consist essentially of," and "consist only of."

In addition, in this specification, when a numerical range is indicated as "A to B," it means A or more and B or less.

The following describes an embodiment of the present invention, but various modifications in form and detail are possible without departing from the spirit and scope of the claims.

1. Hydroxyalkanoate Composition The hydroxyalkanoate composition of the present invention contains an alkali metal hydroxyalkanoate and an alkaline earth metal hydroxyalkanoate,
The hydroxyalkanoate composition contains the alkali metal hydroxyalkanoate in an amount of 1 to 70 mol % in terms of the amount of alkali metal, and the alkaline earth metal hydroxyalkanoate in an amount of 30 to 99 mol % in terms of the amount of alkaline earth metal, where the total amount of alkali metal and alkaline earth metal in the hydroxyalkanoate composition is 100 mol %, and the hydroxyalkanoate composition is amorphous.

(1-1) Hydroxyalkanoic Acid Alkali Metal Salt Examples of the hydroxyalkanoic acid in the hydroxyalkanoic acid alkali metal salt include hydroxyacetic acid, 3-hydroxypropionic acid, 3-hydroxybutyric acid (3HB), 4-hydroxybutyric acid, 3-hydroxyvaleric acid, 3-hydroxyisovaleric acid, 3-hydroxyhexanoic acid, 3-hydroxyheptanoic acid, 3-hydroxyoctanoic acid, and 3-hydroxydecanoic acid. These hydroxyalkanoic acids can be used alone or in combination of two or more. Among these, from the viewpoints of ease of use as an energy source, ease of suppressing fat and sugar absorption, ease of improving cognitive function and long-term memory function, and ease of preventing Alzheimer's disease, 3-hydroxyalkanoic acids having 3 to 12 carbon atoms are preferred, 3-hydroxyalkanoic acids having 3 to 8 carbon atoms are more preferred, 3-hydroxyalkanoic acids having 4 to 6 carbon atoms are even more preferred, and 3-hydroxybutyric acid (3HB) represented by the following formula is most preferred.

Examples of alkali metal salts in alkali metal hydroxyalkanoates include sodium salts, potassium salts, and lithium salts. These alkali metal salts can be used alone or in combination of two or more. When used alone, any alkali metal salt has a relative humidity point in its water vapor adsorption isotherm where the amount of water vapor adsorbed rises significantly (e.g., 45% for sodium salts and 35% for potassium salts). This makes it difficult to manufacture and unsuitable for storage in high-humidity environments. However, by using a mixed salt with an alkaline earth metal salt, adjusting the content within a specific range, and making it amorphous, as in the present invention, the relative humidity point where the amount of water vapor adsorbed rises significantly does not exist, making the salt both manufacturable and easy to store.

Furthermore, when potassium salts are used alone, they are extremely hygroscopic, making them difficult to manufacture. However, by using a mixed salt with an alkaline earth metal salt and setting the content within a specific range, as in the present invention, hygroscopicity is reduced, making production and storage possible, which is particularly useful. This effectively utilizes potassium salts, which account for a large portion of the recommended mineral intake, making it particularly easy to increase the intake of hydroxyalkanoic acids.

For these reasons, preferred alkali metal salts are sodium salts, potassium salts, etc., with potassium salts being more preferred.

The alkali metal hydroxyalkanoates can be used alone or in combination of two or more.

The three-dimensional structure of the alkali metal hydroxyalkanoate may be the R-configuration (R-isomer) or the S-configuration (S-isomer), or both configurations may be mixed in any proportion. From the viewpoints of ease of use as an energy source, ease of suppressing fat and sugar absorption, ease of improving cognitive function and long-term memory function, and ease of preventing Alzheimer's disease, the R-configuration (R-isomer) is preferred, and it is more preferable for the salt to contain 95 to 100 mol% of the R-configuration (R-isomer).

The method for producing the alkali metal hydroxyalkanoate used in the present invention is not particularly limited. Hydroxyalkanoic acid can be produced by a conventionally known method, and the alkali metal hydroxyalkanoate can be further produced by a conventionally used salt formation process, desalting process, salt exchange process, etc.

In the hydroxyalkanoate composition of the present invention, the content of the alkali metal hydroxyalkanoate is 1 to 70 mol%, preferably 5 to 65 mol%, and more preferably 10 to 60 mol%, calculated as the alkali metal amount, with the total amount of alkali metal and alkaline earth metal in the hydroxyalkanoate composition being 100 mol%. Within this range, the hydroxyalkanoate composition does not crystallize and becomes an amorphous material, thereby reducing hygroscopicity. By increasing the content of the alkali metal hydroxyalkanoate as much as possible while satisfying this range, i.e., 20 mol% or more, particularly 30 mol% or more, further 40 mol% or more, and even more particularly 50 mol% or more, it is possible to increase the intake of hydroxyalkanoic acid due to the high recommended intake of alkali metal hydroxyalkanoate. Note that if the content of the alkali metal hydroxyalkanoate is less than 1 mol%, the intake of hydroxyalkanoic acid cannot be increased due to the low content of alkali metal hydroxyalkanoate. On the other hand, if the content of alkali metal hydroxyalkanoate exceeds 70 mol%, the hydroxyalkanoate composition becomes a crystalline material and is highly hygroscopic, making it difficult to manufacture and store.

(1-2) Alkaline Earth Metal Hydroxyalkanoate As the hydroxyalkanoic acid in the alkaline earth metal hydroxyalkanoate, the same hydroxyalkanoic acid as in the above-mentioned alkali metal hydroxyalkanoate may be used, or a different hydroxyalkanoic acid may be used.

Examples of hydroxyalkanoic acids in the alkali metal hydroxyalkanoate salts include hydroxyacetic acid, 3-hydroxypropionic acid, 3-hydroxybutyric acid (3HB), 4-hydroxybutyric acid, 3-hydroxyvaleric acid, 3-hydroxyisovaleric acid, 3-hydroxyhexanoic acid, 3-hydroxyheptanoic acid, 3-hydroxyoctanoic acid, and 3-hydroxydecanoic acid. These hydroxyalkanoic acids can be used alone or in combination of two or more. Among these, from the viewpoints of ease of use as an energy source, ease of suppressing fat and sugar absorption, ease of improving cognitive function and long-term memory function, and ease of preventing Alzheimer's disease, 3-hydroxyalkanoic acids having 3 to 12 carbon atoms are preferred, 3-hydroxyalkanoic acids having 3 to 8 carbon atoms are more preferred, 3-hydroxyalkanoic acids having 4 to 6 carbon atoms are even more preferred, and 3-hydroxybutyric acid (3HB) is most preferred.

Examples of alkaline earth metal salts in alkaline earth metal hydroxyalkanoates include magnesium salts, calcium salts, and barium salts. These alkaline earth metal salts can be used alone or in combination of two or more. For any alkaline earth metal salt, by mixing it with an alkali metal salt and setting the content within a specific range, the amount adsorbed can be reduced compared to the alkali metal salt alone. Since there is no relative humidity point at which the amount of water vapor adsorbed increases significantly, the product can be produced and stored even in high-humidity environments. Furthermore, the inclusion of an alkali metal salt can increase the intake of hydroxyalkanoic acid.

Among these, magnesium salts and calcium salts are preferred as alkaline earth metal salts, with magnesium salts being more preferred.

The alkaline earth metal hydroxyalkanoates can be used alone or in combination of two or more.

The steric structure of the alkaline earth metal hydroxyalkanoate salt may be the R-configuration (R-isomer) or the S-configuration (S-isomer), or both configurations may be mixed in any ratio. From the viewpoints of ease of use as an energy source, ease of suppressing fat and sugar absorption, ease of improving cognitive function and long-term memory function, and ease of preventing Alzheimer's disease, the R-configuration (R-isomer) is preferred, and it is more preferable for the salt to contain 95 to 100 mol% of the R-configuration (R-isomer).

The method for producing the alkaline earth metal hydroxyalkanoate used in the present invention is not particularly limited. Hydroxyalkanoic acid can be produced by a conventionally known method, and then the alkaline earth metal hydroxyalkanoate can be produced by conventionally used salt formation, desalting, salt exchange, etc.

In the hydroxyalkanoate composition of the present invention, the content of the alkaline earth metal hydroxyalkanoate is 30 to 99 mol%, preferably 35 to 95 mol%, and more preferably 40 to 90 mol%, based on 100 mol% of the total amount of alkali metal and alkaline earth metal in the hydroxyalkanoate composition. By minimizing the content of the alkaline earth metal hydroxyalkanoate while remaining within this range, i.e., 80 mol% or less, particularly 70 mol% or less, further 60 mol% or less, and even more particularly 50 mol% or less, it is possible to relatively increase the content of the alkali metal hydroxyalkanoate, which has a high recommended intake, and thereby increase the intake of hydroxyalkanoic acid. Note that if the content of the alkali metal hydroxyalkanoate is less than 30 mol%, the hydroxyalkanoate composition becomes a crystalline material and is highly hygroscopic, making it difficult to manufacture and store. If the content of alkaline earth metal hydroxyalkanoate exceeds 99 mol%, the intake of hydroxyalkanoic acid cannot be increased due to the low content of alkali metal hydroxyalkanoate.

(1-3) Other Components The hydroxyalkanoate composition of the present invention preferably contains other components as appropriate, provided that the components do not impair the objects and effects of the present invention. Such other components are not particularly limited as long as they are edible, and examples thereof include edible oils and fats, proteins, carbohydrates, dietary fiber, etc.

There are no particular restrictions on edible oils and fats, and a wide variety can be used.

Examples of edible fats and oils include vegetable fats such as milk fat, shea butter, olive oil, soybean oil, safflower oil, corn oil, sunflower oil, rapeseed oil, coconut oil, palm oil, palm kernel oil, and fractionated palm oil; and animal fats and oils such as lard and fish oil.

These edible oils and fats also include oils and fats synthesized from glycerin and fatty acids, as well as fractionated oils, interesterified oils, and hydrogenated oils.

Examples of oils and fats synthesized from glycerin and fatty acids include medium-chain triglyceride (MCT) oils and fats.

Examples of fractionated oils include palm oil fractionated oils such as palm olein, palm superolein, palm stearin, and palm mid fraction.

Interesterified oils that can be used include, for example, interesterified oils of the above-mentioned oils and fats or their fractionated oils with other liquid oils and fats, or interesterified oils of medium-chain triglyceride (MCT) oils and vegetable oils, etc.

Hydrogenated oils include hydrogenated oils of the above-mentioned fats and oils and their fractionated oils, as well as hydrogenated oils of interesterified oils.

These edible oils and fats also include refined oils and fats. When refined oils and fats are used, the refining method for the oils and fats is not particularly limited, but examples include chemical refining and physical refining. Chemical refining is a method in which crude oil pressed and extracted from raw materials is refined by subjecting it to degumming, deacidification, bleaching, dewaxing, deodorization, etc. Physical refining is a method in which crude oil pressed from raw materials is refined by subjecting it to degumming, bleaching, deacidification and deodorization, etc.

These edible oils and fats can be used alone or in combination of two or more.

Furthermore, there are no particular restrictions on the form of these edible oils and fats, as long as the composition is solid.

There are no particular limitations on the protein, and whey protein, casein protein, soy protein, pea protein, wheat protein, egg protein, rice protein, etc. can all be used. In the present invention, not only water-soluble whey proteins such as whey protein, but also water-insoluble proteins can improve the water dispersibility while suppressing the deliquescence and sourness of 3HB. Of these, whey protein, casein protein, soy protein, etc. are preferred from the standpoints of water dispersibility, suppression of deliquescence, suppression of sourness, etc., and whey protein is more preferred.

These proteins may be partially hydrolyzed to improve their water dispersibility and absorbability. Specific examples of such partially hydrolyzed proteins include water-soluble protein hydrolyzates obtained by partially hydrolyzing the proteins contained in a protein raw material using a protease, acid, etc.

The protein is preferably in powder form when used. Examples of protein forms include pulverized, powdered, powdered, flakes, granular, and particulate forms, and the individual forms are not strictly limited.

The above proteins are not particularly limited, and publicly known or commercially available products can be used.

Carbohydrates usually refer to carbohydrates other than dietary fiber. Examples of carbohydrates include edible sugars such as monosaccharides, disaccharides, oligosaccharides, sugar alcohols, isomerized sugar, and starch hydrolysates. More specific examples include glucose (monosaccharide), table sugar, maltose, lactose, trehalose (all disaccharides), maltitol, palatinit (all sugar alcohols), glucose-fructose syrup, fructose-glucose syrup (all isomerized sugar), starch syrup (a mixture of glucose, maltose, and dextrin), and dextrin (a starch hydrolysate).

Examples of dietary fiber include wheat bran, corn bran, oat bran, cellulose-based fibers extracted from plants (e.g., corn fiber, soybean dietary fiber, beet fiber, etc.), cellulose, crystalline cellulose, agar, chitosan, chitin, hemicellulose, lignin, glucan, etc.

When these other components are included, their content is preferably within a range that does not impair the objectives and effects of the present invention. However, since the present invention enables the production and storage of a hydroxyalkanoate composition with reduced hygroscopicity without using other components, and it is expected that the intake of hydroxyalkanoic acid will be increased by increasing the content of hydroxyalkanoic acid alkali metal salts, which have a high recommended intake amount, as much as possible, it is preferable that the content of these other components be as low as possible. For example, from the standpoints of hygroscopicity, deliquescence suppression, acidity suppression, hydroxyalkanoic acid intake, etc., the content of components other than the hydroxyalkanoate composition of the present invention is preferably 0 to 10% by mass, and more preferably 0.01 to 5% by mass, of the total amount of the hydroxyalkanoate composition of the present invention, taken as 100% by mass.

(1-4) Hydroxyalkanoate Composition The hydroxyalkanoate composition of the present invention having the above-mentioned components can be an amorphous material, unlike an alkali metal hydroxyalkanoate salt alone.

In the present invention, a hydroxyalkanoate composition being an amorphous material means that it does not have peaks characteristic of alkali metal hydroxyalkanoates in its X-ray diffraction pattern using CuKα radiation. Specifically, it is preferable that it does not have peaks with a full width at half maximum of 0.50° or less (preferably 0.01 to 0.50°, more preferably 0.03 to 0.40°, and even more preferably 0.05 to 0.25°) within an acceptable range of ±0.5° (preferably ±0.3°, more preferably ±0.2°), for example, a peak at a diffraction angle 2θ = 6.38° in the case of potassium 3-hydroxybutyrate, or a peak at diffraction angles 2θ = 6.70° or 7.08° in the case of sodium 3-hydroxybutyrate.

In the present invention, the hydroxyalkanoate composition is an amorphous material when, in an X-ray diffraction pattern using CuKα rays, the area of the halo in the range of 5 to 85° is defined as (S1), and the area of the peak beyond the halo, which is attributable to the hydroxyalkanoate composition in a crystalline state, is defined as (S2).
Formula: [(S2)/(S1)+(S2)]×100
It is preferable that the ratio calculated by is 0 to 5%, particularly 0 to 3%, and further preferably 0 to 2%.

In addition, in the present invention, it is preferable that only a halo is present in the range of 5 to 85° in the X-ray diffraction pattern using CuKα radiation. In this case, the crystallinity of the composition can be reduced (increased amorphousness), which in turn can reduce the adsorption properties of the composition.

The hydroxyalkanoate composition of the present invention can be in the form of a solid or a liquid (aqueous dispersion). That is, it can be stored as a solid such as a powder and taken orally as is or in combination with water, or it can be dispersed in water and taken orally as an aqueous dispersion.

In any case, since it can reduce hygroscopicity and can be stored without strict monitoring, it is suitable for oral ingestion, and since it allows for the optimal intake of hydroxyalkanoic acid, which is an energy source, it is useful as a nutritional supplement, etc.

2. Method for Producing Hydroxyalkanoate Composition The method for producing the hydroxyalkanoate composition of the present invention comprises the steps of:
The method includes a step of mixing a hydroxyalkanoic acid with an alkali metal and an alkaline earth metal in a solution, and adjusting the content of the alkali metal in the mixed solution to 1 to 70 mol % and the content of the alkaline earth metal salt in the mixed solution to 30 to 99 mol %, where the total amount of the alkali metal and alkaline earth metal is 100 mol %.

In this case, the liquid component of the solution when mixing the hydroxyalkanoic acid with the alkali metal and alkaline earth metal can be one or more of various solvents (preferably polar solvents, more preferably water) such as water or alcohol (e.g., ethanol), and is not particularly limited.

There are no particular limitations on the mixing method, and mixing can be carried out using any known method. For example, mechanical mixing using a mixer or mill can be used.

Furthermore, when mixing hydroxyalkanoic acid with an alkali metal and an alkaline earth metal in a solution, there are no particular limitations, and for example, a hydroxyalkanoic acid solution can be mixed with a mixed solution of an alkali metal and an alkaline earth metal. For example, a solution containing an alkali metal and an alkaline earth metal (preferably an aqueous solution containing an alkali metal and an alkaline earth metal) can be added dropwise to a hydroxyalkanoic acid solution (preferably an aqueous solution of hydroxyalkanoic acid), or a hydroxyalkanoic acid solution (preferably an aqueous solution of hydroxyalkanoic acid) can be added dropwise to a solution containing an alkali metal and an alkaline earth metal (preferably an aqueous solution containing an alkali metal and an alkaline earth metal).

When the hydroxyalkanoate composition of the present invention is a solid, the solvent can be removed and the solid isolated by conventional methods such as concentration and/or drying. Examples of such methods include, but are not limited to, evaporating (volatilizing) the solvent remaining in the mixture using an evaporator, spray dryer, freeze dryer, etc., and then filtering the resulting solid or drying it under reduced pressure.

On the other hand, the method for producing a hydroxyalkanoate composition of the present invention comprises the steps of:
The method may also include a step of melting a mixture containing a solid hydroxyalkanoic acid alkali metal salt and a solid hydroxyalkanoic acid alkaline earth metal salt, and adjusting the alkali metal content of the mixture to 1 to 70 mol % and the alkaline earth metal salt content to 30 to 99 mol %, where the total amount of the alkali metal and alkaline earth metal is 100 mol %.

In this case, the mixture can be melted in the presence or absence of one or more small amounts (approximately 1 to 20 parts by mass per 100 parts by mass of the mixture) of water or alcohol (e.g., ethanol).

The mixture used as a raw material may further contain a hydroxyalkanoic acid. In this case, it is preferable to adjust the final composition to be the same as the hydroxyalkanoate composition of the present invention.

It is also possible to pre-mix the hydroxyalkanoic acid alkali metal salt solid and the hydroxyalkanoic acid alkaline earth metal salt solid before melting.

The mixing method is not particularly limited, and any known method can be used. For example, mechanical mixing using a mixer or mill can be used.

The above describes embodiments of the present invention, but the present invention is not limited to these examples and can, of course, be embodied in various forms without departing from the spirit of the present invention.

The following provides a more detailed explanation of embodiments of the present invention based on examples, but the present invention is not limited to these examples.

In the following examples, (R)-3-hydroxybutyric acid was obtained by concentrating an aqueous solution of R-3-hydroxybutyric acid, produced according to the method described in Example 1 of JP 2019-176839 A, in an evaporator set at 70°C until no water was released, adding 30% by mass of ethyl acetate and seed crystals of R-3-hydroxybutyric acid based on the weight of the concentrated solution, and leaving it at 4°C overnight. This solution was filtered and dried and used in the following examples.

<Analysis method>
Powder X-ray Diffraction Measurement Using a fully automated multipurpose horizontal powder X-ray diffractometer SmartLab (manufactured by Rigaku Corporation), measurements were taken using CuKα (λ=1.542 Å) as the radiation source at an output of 1.2 kW and an operating angle of 5 to 85°.

Comparative example 1: 3HB-K
20 g (0.19 mol) of R-3-hydroxybutyric acid (R-3HB) and 30 g of distilled water were placed in a beaker and mixed to prepare an R-3HB aqueous solution. 20 g of distilled water was placed in a separate beaker, and 10.7 g (0.20 mol) of potassium hydroxide was added and mixed. A potassium hydroxide aqueous solution was added dropwise to the R-3HB aqueous solution to adjust the pH to 9. Distilled water was added to the R-3HB aqueous solution to a weight of 136.1 g and a solids content of approximately 20% by mass. This was dried using a spray dryer to obtain a powder of the potassium salt of R-3HB. A B-290 spray dryer manufactured by Nippon Buchi was used.

The powder X-ray diffraction pattern of the obtained sample showed the following diffraction peaks derived from the crystals of the potassium salt of R-3HB:
Diffraction angles 2θ = 6.38° (full width at half maximum 0.10°), 7.14°, 12.76°, 18.20°, 19.26°, 19.52°, 20.82°, 22.46°, 25.76°, 26.78°, 30.02°, 31.10°, 31.84°, 32.28°, 32.38°, 35.12°.

Comparative example 2: 3HB-Ca
In Comparative Example 1, the base used was changed from potassium hydroxide to calcium hydroxide, and a 20% by mass solution of pH 7 was prepared and dried in the same manner to obtain a powder of calcium salt of R-3HB. The powder X-ray diffraction pattern of the obtained sample showed only the following halo, which is characteristic of an amorphous phase and is derived from the calcium salt of R-3HB:
Diffraction angle 2θ=7.16° (full width at half maximum 2.62°), 21.46° (full width at half maximum 12.56°).

Comparative example 3: 3HB-Mg
In Comparative Example 1, the base used was changed from potassium hydroxide to magnesium oxide, and a 20% by mass solution of R-3HB at pH 7 was prepared in the same manner as in Comparative Example 1, followed by drying to obtain a powder of the magnesium salt of R-3HB. The powder X-ray diffraction pattern of the obtained sample showed only the following halo, which is characteristic of an amorphous phase and is derived from the magnesium salt of R-3HB:
Diffraction angle 2θ=8.00° (full width at half maximum 3.70°), 21.14° (full width at half maximum 13.00°).

Comparative example 4: 3HB-Na
In Comparative Example 1, the base used was changed from potassium hydroxide to sodium hydroxide, and a 20% by mass solution of R-3HB at pH 7 was prepared in the same manner as in Comparative Example 1, followed by drying to obtain a powder of the sodium salt of R-3HB. The powder X-ray diffraction pattern of the obtained sample showed the following diffraction peaks derived from crystals of the sodium salt of R-3HB:
Diffraction angles 2θ = 6.70° (full width at half maximum 0.18°), 7.08° (full width at half maximum 0.18°), 8.34°, 11.68°, 12.08°, 16.86°, 18.76°, 20.20°, 20.64°, 20.68°, 22.08°, 22.44°, 23.14°, 23.44°, 27.60°, 28.80°, 28.88°, 29.40°, 30.00°, 30.20°, 30.26°, 30.50°, 33.18°, 37.06°.

Example 1: 3HB-KCa
20 g (0.19 mol) of R-3-hydroxybutyric acid (R-3HB) and 30 g of distilled water were mixed in a beaker to prepare an R-3HB aqueous solution. 20 g of distilled water was placed in a separate beaker, and 4.88 g (0.066 mol) of calcium hydroxide and 3.70 g (0.066 mol) of potassium hydroxide were added and mixed. A mixed aqueous solution of potassium hydroxide and calcium hydroxide was added dropwise to the R-3HB aqueous solution, and the pH was adjusted to 9. Distilled water was added to the R-3HB aqueous solution to adjust the weight to 124.3 g and the solids content to approximately 20% by mass. This was dried using a spray dryer to obtain a powder of a potassium and calcium mixed salt of R-3HB, with a potassium to calcium molar ratio of 1:1. A B-290 spray dryer manufactured by Nippon Buchi was used.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only the following halo characteristic of an amorphous substance, which was due to the potassium and calcium mixed salt of R-3HB:
Diffraction angle 2θ=6.90° (full width at half maximum 2.22°), 21.30° (full width at half maximum 8.98°).

Example 2: 3HB-KMg 1:1
The calcium hydroxide used in Example 1 was changed to magnesium oxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of potassium and magnesium of R-3HB, in which the molar ratio of potassium to magnesium was 1:1.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only the following halo characteristic of an amorphous substance, which was due to the potassium and magnesium mixed salt of R-3HB:
Diffraction angle 2θ=6.90° (full width at half maximum 3.18°), 21.36° (full width at half maximum 13.54°).

Comparative example 5: 3HB-KNa
The calcium hydroxide used in Example 1 was changed to sodium hydroxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of potassium and sodium of R-3HB in which the molar ratio of potassium to sodium was 1:1.

The powder X-ray diffraction pattern of the obtained sample showed the following diffraction peaks derived from crystals of a mixed salt of potassium and sodium R-3HB:
Diffraction angles 2θ = 6.54° (full width at half maximum 0.18°), 6.80° (full width at half maximum 0.10°), 13.62°, 13.80°, 18.26°, 18.80°, 19.98°, 20.42°, 20.78°, 21.56°, 21.90°, 22.56°, 23.36°, 23.58°, 24.38°, 24.90°, 25.76°, 25.96°, 26.32°, 26.36°, 26.42°, 26.52°, 27.08°, 27.16°, 27.40°, 27.72°, 29.20°, 29.82°, 29.86°, 29.94°, 30.08°, 31.18°, 31.26°, 31.32°, 31.48°, 31.80°, 31.90°, 32.02°, 32.06°, 32.1°, 32.18°, 32.32°, 33.82°, 33.90°, 34.00°, 34.06°, 34.42°, 37.02°, 37.54°, 38.22°.

Example 3: 3HB-KMg 1:4
The calcium hydroxide used in Example 1 was changed to magnesium hydroxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of potassium and magnesium of R-3HB in which the molar ratio of potassium to magnesium was 1:4.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only an amorphous halo characteristic of the potassium and magnesium mixed salt of R-3HB was observed.

Example 4: 3HB-KMg 2:3
The calcium hydroxide used in Example 1 was changed to magnesium hydroxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of potassium and magnesium of R-3HB in which the molar ratio of potassium to magnesium was 2:3.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only an amorphous halo characteristic of the potassium and magnesium mixed salt of R-3HB was observed.

Example 5: 3HB-KMg 3:2
The calcium hydroxide used in Example 1 was changed to magnesium hydroxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of potassium and magnesium of R-3HB in which the molar ratio of potassium to magnesium was 3:2.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only an amorphous halo characteristic of the potassium and magnesium mixed salt of R-3HB was observed.

Comparative example 6:3HB-KMg4:1
The calcium hydroxide used in Example 1 was changed to magnesium hydroxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of potassium and magnesium of R-3HB in which the molar ratio of potassium to magnesium was 4:1.

The powder X-ray diffraction pattern of the obtained sample showed the following diffraction peaks derived from crystals of the potassium and magnesium mixed salt of R-3HB:
Diffraction angle 2θ=6.38° (full width at half maximum 0.22°), 6.60° (full width at half maximum 0.14°).

Example 6: 3HB-NaCa
The potassium hydroxide used in Example 1 was changed to sodium hydroxide, and a 20% by mass solution of pH 9 was similarly prepared and dried, thereby obtaining a powder of a mixed salt of sodium and calcium of R-3HB in which the molar ratio of sodium to calcium was 1:1.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only an amorphous halo characteristic of the sodium and calcium mixed salt of R-3HB was observed.

Example 7: 3HB-NaMg
The potassium hydroxide used in Example 1 was changed to sodium hydroxide, and the calcium hydroxide was changed to magnesium hydroxide. Similarly, a 20% by mass solution of pH 9 was prepared and dried, thereby obtaining a powder of a mixed salt of sodium and magnesium of R-3HB in which the molar ratio of sodium to magnesium was 1:1.

The powder X-ray diffraction pattern of the obtained sample showed no diffraction due to crystals, and only an amorphous halo characteristic of the sodium and magnesium mixed salt of R-3HB was observed.

Test Example 1: Hygroscopicity Test (Part 1)
1 g of each of the powders obtained in Examples 1 and 2 and Comparative Examples 1 to 5 was stored in a thermo-hygrostat at 25°C and 40% humidity for 20 hours, and the weight gain was measured to compare the hygroscopicity. The results are shown in Figure 1.

As a result, it can be seen that the potassium salt of Comparative Example 1 is highly hygroscopic and unsuitable for storage. Furthermore, while the sodium salt of Comparative Example 4 had low hygroscopicity, its mixed salt with potassium exhibited high hygroscopicity, and mixing potassium and sodium did not result in a reduction in hygroscopicity. In contrast, Examples 1 and 2 used mixed salts of potassium and magnesium or calcium, i.e., mixed salts of alkali metals and alkaline earth metals, which significantly reduced hygroscopicity compared to potassium salt alone. In particular, the potassium and calcium mixed salt of Example 1 was able to reduce hygroscopicity to the same level or even greater than the calcium salt and magnesium salt of Comparative Examples 2 and 3. Therefore, the present invention, which uses mixed salts of alkali metals and alkaline earth metals, significantly reduced hygroscopicity and is suitable for production and storage, and is expected to increase the intake of hydroxyalkanoic acid because it contains alkali metal salts with a high recommended intake amount.

Test Example 2: Hygroscopicity Test (Part 2)
1 g of each of the powders obtained in Examples 2 to 5 and Comparative Examples 1, 3, and 6 was stored in a thermo-hygrostat at 25°C and 40% humidity for 20 hours, and the weight gain was measured to compare the hygroscopicity. The results are shown in Figure 2.

As a result, in Examples 2 to 5, the magnesium content was sufficient, and thus hygroscopicity was similarly reduced; however, in Comparative Example 6, the magnesium content was insufficient, and therefore the effect of reducing hygroscopicity was not sufficient. Therefore, in the present invention, the alkali metal and alkaline earth metal contents are set within a specified range, thereby significantly reducing hygroscopicity, making it suitable for manufacturing and storage, and since it contains alkali metal salts with a high recommended intake amount, it is expected to increase the intake of hydroxyalkanoic acid.

Test Example 3: Water Vapor Adsorption Isotherm Using a high-precision vapor adsorption measuring device BELSORP-aqua3 (manufactured by Microtrac BEL Co., Ltd.), water vapor adsorption isotherms were measured at 25°C and an equilibrium waiting time of 300 seconds for the powders obtained in Examples 1 to 2, 6 to 7, and Comparative Examples 1 and 4 to 5. The results are shown in Figures 3 and 4.

As a result, in Comparative Examples 1, 4, and 5, there was a relative humidity point at which the amount of adsorption increased significantly, but in Examples 1-2 and 6-7, no such tendency was observed, and the amount of adsorption increased gradually. Therefore, the present invention is suitable for production and storage even in high-humidity environments, and because it contains alkali metal salts with a high recommended intake amount, it is expected to increase the intake of hydroxyalkanoic acids.

Claims (12)

A 3-hydroxybutyrate composition containing an alkali metal salt of 3-hydroxybutyrate and an alkaline earth metal salt of 3-hydroxybutyrate ,
The content of the alkali metal salt of 3-hydroxybutyric acid is 20 to 60 mol % in terms of the amount of alkali metal, and the content of the alkaline earth metal salt of 3-hydroxybutyric acid is 40 to 80 mol % in terms of the amount of alkaline earth metal, where the total amount of the alkali metal and alkaline earth metal is 100 mol %; and
is amorphous,
3-hydroxybutyrate composition. 2. The 3-hydroxybutyrate composition according to claim 1, wherein the alkali metal 3-hydroxybutyrate is at least one selected from the group consisting of sodium, potassium, and lithium salts of 3-hydroxybutyrate . 3. The 3-hydroxybutyrate composition according to claim 1, wherein the alkaline earth metal salt of 3-hydroxybutyric acid is at least one selected from the group consisting of magnesium salt, calcium salt, and barium salt of 3-hydroxybutyric acid . The 3-hydroxybutyrate composition according to any one of claims 1 to 3, wherein, in an X-ray diffraction pattern using CuKα radiation, there is no peak at a diffraction angle 2θ = 6.38° with a full width at half maximum of 0.50° or less, or there are no peaks at diffraction angles 2θ = 6.70° and 7.08° with a full width at half maximum of 0.50° or less, within a tolerance range of ± 0.5 °. Alternatively, there is only a halo. 5. The 3-hydroxybutyrate composition according to claim 1 , wherein the alkali metal 3- hydroxybutyrate and the alkaline earth metal 3-hydroxybutyrate contain an R configuration. The 3-hydroxybutyrate composition according to any one of claims 1 to 5 , which is a 3-hydroxybutyrate composition for oral administration. A nutritional supplement comprising the 3-hydroxybutyrate composition according to any one of claims 1 to 6 . A method for producing the 3-hydroxybutyrate composition according to any one of claims 1 to 6 or the dietary supplement according to claim 7 , comprising:
The method comprises the step of mixing 3-hydroxybutyric acid with an alkali metal and an alkaline earth metal in a solution,
and adjusting the content of the alkali metal in the mixed aqueous solution to 20 to 60 mol % and the content of the alkaline earth metal salt in the mixed solution to 40 to 80 mol %, where the total amount of the alkali metal and alkaline earth metal is 100 mol %. The method according to claim 8 , wherein the solvent constituting the solution is a polar solvent. The method according to claim 8 or 9 , wherein the solvent constituting the solution is water. After said mixing,
The method according to any one of claims 8 to 10 , further comprising a step of concentrating and/or drying the resulting mixture. The method according to claim 11 , wherein the drying is carried out by spray drying to obtain a dry powder.