Liquid composition and method for stabilizing the same

Abstract

The present invention provides a liquid composition that can suppress the excessive amount of 3-hydroxybutyric acid, even when it is present. [Solution] A liquid composition is prepared containing 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid, and water. The proportion of the salt of 3-hydroxybutyric acid may be 0.1 to 100 moles per 100 moles of 3-hydroxybutyric acid. The total proportion of 3-hydroxybutyric acid and the salt of 3-hydroxybutyric acid may be 15% by mass or more in the liquid composition, in terms of 3-hydroxybutyric acid in its free form. The 3-hydroxybutyric acid may be R-3-hydroxybutyric acid produced by fermentation using microorganisms. The pH of the liquid composition may be 2.2 or higher. The liquid composition may be a beverage or its concentrate.

Description

Technical Field

[0001] The present invention relates to a liquid composition containing 3-hydroxybutyric acid (hereinafter sometimes simply referred to as "3HB") and a method for stabilizing the same.

Background Art

[0002] 3HB and its salts are substances present in the human body and are expected as a revolutionary energy source to replace carbohydrates. Further, 3HB is not only a role as an energy source, but it has also been confirmed to be effective in improving cognitive function, enhancing long-term memory, and preventing Alzheimer's disease. Furthermore, 3HB can also be produced in the body by ingesting food. For example, by ingesting and metabolizing medium-chain fatty acids (MCT) contained in coconut oil and the like, it is taken into the blood and converted into energy. This process has the effect of being able to convert energy more quickly than carbohydrates via the glycolysis system, and also has the effect of suppressing the absorption of fat and sugar, thereby suppressing the absorption of fat and sugar into cells. Therefore, 3HB is expected to be applied to energy substances for athletes and the fields of diet and health foods.

[0003] Such 3HB is extremely sour in acid form, so it is difficult to ingest in large amounts, and perhaps because of this, its spread has not advanced. Further, 3HB is difficult to prepare as a highly fluid powdery solid in acid form and has problems in handling. 3HB does not easily crystallize even when water is removed from an aqueous solution state, and when removing water, it easily polymerizes by condensation reaction and changes to a dimer or the like, so it is difficult to isolate as a solid. ​​​​​​​​​​​​​This is the cause. Therefore, generally speaking, 3HB is not an acid, but sodium, calcium It is provided as a powder in the form of neutralized salts such as magnesium.

[0004] However, consuming large amounts of 3HB neutralized salt can lead to excessive sodium intake, which can negatively impact diet and health. In the fields of health foods and pharmaceuticals, it is considered undesirable from a health perspective.

[0005] An example of the use of 3HB in the diet and health food sector is Japanese Patent Publication No. 2021-18579. Publication No. 9 (Patent Document 1) describes an oil and fat composition containing 3HB and / or its salt and oil and fat particles. This has been disclosed. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2021-185799 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] However, the composition described in Patent Document 1 tends to be avoided in the diet and health food sector. Oils and fats are essential components. Also, because it is in solid form, it is not suitable for use as a liquid such as in beverages. It is not suitable. Furthermore, according to the inventors' investigations, 3HB is in the state of an aqueous solution. In its current state, just as volume increases due to the removal of moisture, volume also increases during storage, especially, It was found that the process proceeds easily when the concentration of the aqueous solution is increased. When the quantification progresses, during storage Furthermore, the concentration and pH of the aqueous solution change over time, leading to problems with stable quality. For example, refreshing For drinking water, pH affects the shelf life, so it is necessary to avoid pH changes during storage. . Therefore, even if it contains 3HB in a free form, it is required to have a stabilization method that can suppress the increase in the amount of 3HB in an aqueous solution during storage. A stabilization method that can suppress the increase in the amount of 3HB is required.

[0008] Therefore, an object of the present invention is to provide a liquid composition that can suppress the polymerization of 3-hydroxybutyric acid even if it contains 3-hydroxybutyric acid, and a method for stabilizing the same. A liquid composition that can suppress the polymerization of 3-hydroxybutyric acid and a method for stabilizing the same are provided. <000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​It is an embodiment in which the content is adjusted to 15% by mass or more in the liquid composition in terms of 3-hydroxybutyric acid.

[0013] Aspect [4] of the present invention is the liquid composition after pH adjustment in aspect [1], and the total proportion of 3-hydroxybutyric acid and salts of 3-hydroxybutyric acid is adjusted to less than 15% by mass in the liquid composition in terms of 3-hydroxybutyric acid in the free form. It is an embodiment in which the total proportion of 3-hydroxybutyric acid and salts of 3-hydroxybutyric acid is adjusted to less than 15% by mass in the liquid composition in terms of 3-hydroxybutyric acid in the free form. It is an embodiment in which the total proportion of 3-hydroxybutyric acid and salts of 3-hydroxybutyric acid is adjusted to less than 15% by mass in the liquid composition in terms of 3-hydroxybutyric acid in the free form.

[0014] Aspect [5] of the present invention is an aspect in any of aspects [1] to [4], in which the 3-hydroxybutyric acid is R-3-hydroxybutyric acid. It is an aspect in which the 3-hydroxybutyric acid is R-3-hydroxybutyric acid.

[0015] <0,000,103>Aspect [6] of the present invention is an aspect in any of aspects [1] to [5], in which the pH of the liquid composition is adjusted to 2.2 or more. It is an aspect in which the pH of the liquid composition is adjusted to 2.2 or more.

[0016] The present invention also includes, as aspect [7], a method of adding a basic compound to a liquid composition containing 3-hydroxybutyric acid and water to suppress the polymerization of the 3-hydroxybutyric acid. It also includes a method of adding a basic compound to a liquid composition containing 3-hydroxybutyric acid and water to suppress the polymerization of the 3-hydroxybutyric acid.

[0017] The present invention also includes, as aspect [8], a liquid composition containing a partially neutralized salt of 3-hydroxybutyric acid (that is, 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid) and water. It also includes a liquid composition containing a partially neutralized salt of 3-hydroxybutyric acid (that is, 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid) and water.

[0018] Aspect [9] of the present invention is an aspect in aspect [8], in which the proportion of the salt of 3-hydroxybutyric acid is 0.1 to 100 moles with respect to 100 moles of the 3-hydroxybutyric acid. It is an aspect in which the proportion of the salt of 3-hydroxybutyric acid is 0.1 to 100 moles with respect to 100 moles of the 3-hydroxybutyric acid.

[0019] Aspect

[10] of the present invention is an aspect in aspect [8] or [9], in which the total proportion of the 3-hydroxybutyric acid and the salt of the 3-hydroxybutyric acid is 3-hydroxybutyric acid in the free form. It is an aspect in which the total proportion of the 3-hydroxybutyric acid and the salt of the 3-hydroxybutyric acid is 3-hydroxybutyric acid in the free form. This embodiment involves the amount being 15% by mass or more in terms of butyric acid in the liquid composition.

[0020] Aspect

[11] of the present invention is an embodiment of any of the above embodiments [8] to

[10] , 3-hydroxybutyric acid is R-3-hydroxybutyric acid produced by fermentation by microorganisms, and the preceding This embodiment describes a liquid composition in which the pH is 2.2 or higher.

[0021] Aspect

[12] of the present invention is a liquid composition of any of the above aspects [8] to

[11] . , in the form of a beverage or its concentrate.

[0022] The present invention, in aspect

[13] , comprises 3-hydroxybutyric acid and water, and has a pH of 2 Liquid compositions meeting the above criteria are also included.

[0023] Aspect

[14] of the present invention is a part of aspect

[13] that includes a salt of 3-hydroxybutyric acid. Furthermore, the pH is 2.2 or higher. [Effects of the Invention]

[0024] In this invention, by adjusting the pH of a liquid composition containing 3-hydroxybutyric acid and water, This suppresses the excessive production of 3-hydroxybutyric acid. In particular, when a basic compound is added to the liquid composition... By adding it to partially neutralize the 3-hydroxybutyric acid and adjust the pH to a higher level, 3-H Even at high concentrations of hydroxybutyric acid, the excess amount of 3-hydroxybutyric acid can be suppressed, improving storage stability. It can be improved. Furthermore, because it is partial neutralization, it can be used in food and pharmaceutical applications without causing excessive salt intake. It can prevent it from happening. [Brief explanation of the drawing]

[0025] [Figure 1]Figure 1 is a graph comparing the storage stability of the 3HB-containing aqueous solutions prepared in Example 1 and Reference Examples 1-7. [Figure 2] Figure 2 is a graph comparing the storage stability of the 3HB-containing aqueous solutions prepared in Examples 5-9. [Figure 3] Figure 3 is a graph comparing the storage stability of the 3HB-containing aqueous solutions prepared in Examples 10-14. [Figure 4] Figure 4 is a graph comparing the storage stability of the 3HB-containing aqueous solutions prepared in Reference Example 11 and Examples 15-18. [Figure 5] Figure 5 is a graph comparing the storage stability of the 3HB-containing aqueous solutions prepared in Reference Example 12 and Examples 19-22. [Modes for carrying out the invention]

[0026] [Method for stabilizing liquid compositions] In the method of the present invention, 3-hydroxybutyric acid (3HB) is used in a liquid composition containing water. Even if present in the form of free acid, by adjusting the pH of the liquid composition, 3HB This can suppress the condensation of molecules, which can lead to dimerization, trimerization, and other forms of polymerization. Below are the three free forms. Sometimes HB is simply referred to as "3HB," and 3HB in salt form is called "3HB salt."

[0027] (Method for adjusting pH) In the method of the present invention, the method for adjusting pH is to adjust the pH to a predetermined pH. This improves the storage stability of the liquid composition, and because volume increases easily at low pH levels. If the pH of the liquid composition is low, raising the pH will improve the storage stability of the liquid composition. Qualitative analysis can be improved. On the other hand, if the concentration of 3HB is low and the pH is sufficiently high, merization will progress. You may increase the concentration to a degree that does not cause the pH to drop. When the concentration of 3HB is increased, the liquid mixture This can improve the transportability and storage efficiency of finished products (space saving in warehouses, etc.).

[0028] The pH of the liquid composition after pH adjustment may be 2 or higher (especially 2.2 or higher), and 2.2~ It can be selected from a range of about 7, for example 2.3 to 6, preferably 2.4 to 5.5, even more preferably The pH is 2.5 to 5, more preferably 3 to 4.5, and most preferably 3.3 to 4. If the level is too low, the amount of 3HB tends to increase, and the acidity becomes strong, affecting foods and pharmaceuticals. This may reduce its palatability. Conversely, if the pH is too high, the taste will become less mellow, and the palatability may decrease. There is a risk that its efficacy as a product or medicine may decrease.

[0029] In this specification and in the claims, pH may be measured by conventional methods, for example. It can be measured using a commercially available pH meter.

[0030] In the method of the present invention, a method for adjusting the pH of the liquid composition is, for example, basicization. A method of adding a compound to partially neutralize 3HB and raise the pH (partial neutralization method), 3HB Methods such as adjusting the concentration to raise the pH (concentration adjustment method) are examples of these methods. Of these, a method using at least partial neutralization is preferred, and a method of adjusting the concentration is preferred. A method combining these two is particularly preferable.

[0031] In this invention, by adjusting the pH of the liquid composition to a high level using a partial neutralization method, the liberated substances are released. In a liquid composition containing 3HB, which is an acid, long-term storage, high temperatures, high concentrations, etc. Even in situations where the quantification of is likely to progress, the quantification of 3HB can be suppressed. Therefore, in the partial... By using the summing method, the concentration of 3HB in the liquid composition can be increased. In the method of the present invention, by using a partial neutralization method, a liquid composition with a high concentration of 3HB is obtained. Because it improves storage stability, it can improve the transportability and storage properties of liquid compositions containing 3HB.

[0032] Therefore, in the liquid composition after pH adjustment, the total proportion of 3HB and 3HB salt is adjusted. In terms of 3HB, which is the form of separation, 15% by mass or more (especially 20% by mass or more) of the liquid composition. It may be adjusted to, for example, 15-70% by mass (for example, 20-50% by mass), preferably 2 0-60% by mass (e.g., 20-40% by mass), more preferably 25-55% by mass, Preferably, it may be adjusted to 30-50% by mass, most preferably 35-45% by mass. In the process, the pH of the liquid composition is adjusted using a partial neutralization method, and the liquid composition contains the aforementioned When the total proportion is adjusted to the aforementioned range, the combination of pH and the concentrations of 3HB and 3HB salts is This method most effectively suppresses the excessive production of 3HB.

[0033] On the other hand, as a method for adjusting pH, pH can be adjusted using only the concentration adjustment method without using the partial neutralization method. The pH may be adjusted, in which case, in the liquid composition after pH adjustment, 3HB and 3HB salt The total proportion is adjusted to less than 15% by mass in the liquid composition, calculated on a free form (3HB). This may be done, for example, 0.1 to 14% by mass, preferably 1 to 13% by mass, and more preferably The amount is 2 to 12% by mass, more preferably 3 to 11% by mass, and most preferably 5 to 10% by mass. .

[0034] Furthermore, in this specification and the claims, "in terms of 3HB equivalent in a free form" means This means converting 3HB salts to 3HB, which is the acid form. For example, 3-H In the case of sodium hydroxybutyrate, convert it to the mass of 3-hydroxybutyrate, which is approximately 3HB. Calculate the total percentage of 3HB salts.

[0035] In the partial neutralization method, after adding a basic compound to the liquid composition, conventional methods, such as mechanical methods, are used. By stirring using conventional means, etc., 3HB and the basic compound are mixed in the liquid composition. It may be mixed uniformly.

[0036] (3-hydroxybutyric acid and its salts) 3HB (or BHB) may be an optical isomer (R-isomer or S-isomer), and is a racemic mixture. This may be acceptable, but from the standpoint of biocompatibility, the R-isomer (R-3-hydroxybutyrate) is used in smaller quantities. It is preferable to include at least one of the 3HB compounds. Of the 3HB compounds, only the R-isomer acts as the active ingredient.

[0037] The proportion of the R-isomer in 3HB, in particular, the optical purity (enantiomer or optical isomer excess), for example, 50% ee or more (for example, 80% ee or more), preferably 90% ee or more (e.g. For example, 95-100% ee), more preferably 98-100% ee (for example, 99 ~100% ee, especially virtually 100% ee). If the optical purity is too low, To ensure sufficient amounts of the target active ingredient due to reduced biocompatibility, a large amount of 3HB and This could lead to an increased need for salt and a risk of excessive salt intake, as well as a rise in 3HB concentration and increased volume. There is a risk that it may become easier.

[0038] Furthermore, the R-form [(R)3HB] and the S-form [(S)3HB] and / or racemic mixture are combined. They may be used together, but the mass proportion of the R-isomer in 3HB is preferably 10% by mass or more. More preferably 50% by mass or more, more preferably 90% by mass or more, and most preferably 10% It is 0% by mass. If the proportion of the R-isomer is high, biocompatibility may be a concern when used as a food or pharmaceutical. Because of its high efficacy, 3HB can efficiently express its function in vivo. Therefore, 3HB is considered a racemic protein. Compared to using the whole body, the concentration of 3HB in the composition can be reduced, and a partial neutralization method is used. Even if salt is generated, the total amount of salt in the composition can be reduced, thereby suppressing excessive salt intake.

[0039] Commercially available 3HB can be used. Commercially available options include chemically synthesized 3HB, and fine Examples include 3HB produced by biological fermentation. Among these, the R-isomer has a high purity. Therefore, fermented 3HB (fermented 3HB) is preferred, and biomass raw materials (biologically derived 3HB produced by fermentation using microorganisms (resources) is particularly preferred. Fermentation-derived 3HB is 3HB contains amino acids and organic acids (lactic acid, acetic acid, pyruvic acid, etc.) produced during the fermentation process. It may be incorporated into a liquid composition as part of the composition. Such a 3HB composition is chemically synthesized. Compared to 3HB, not only is the proportion of the R-isomer increased, but the taste tends to become milder. It is easily ingested as a food or medicine, such as in beverages.

[0040] The liquid composition may further contain a 3HB salt in addition to 3HB. The 3HB salt is p It may also be a salt contained in the liquid composition before H adjustment, and neutralization can be performed using a neutralization method such as partial neutralization. The salt may also be a salt included in the pH-adjusted liquid composition as a salt produced by summation. 3H If the B salt is a salt included in the liquid composition before pH adjustment, then the R-isomer of the 3HB salt is also preferred. i. Of these, the liquid composition has the advantage of improving storage stability even at high concentrations of 3HB. Therefore, it is preferable that the 3HB salt includes at least a 3HB salt obtained by the partial neutralization method. It is particularly preferable that the liquid composition consists only of the 3HB salt obtained by the partial neutralization method. That is, the liquid composition In particular, it is preferable that the form of 3HB is a partially neutralized salt.

[0041] Examples of salt types include alkali gold salts such as sodium salts, potassium salts, and lithium salts. Alkaline earth metal salts; magnesium salts, calcium salts, and other alkaline earth metal salts; ammonium salts; ammonium salts; Examples include salts with basic amino acids. These 3HB salts can be used alone or in pairs. These can be used in combination. Among these, alkalis such as sodium salts and potassium salts are available. Metal salts; alkaline earth metal salts such as magnesium salts and calcium salts are preferred. Potassium salts are preferable because they help to suppress excessive salt intake. Furthermore, they have relatively low deliquescence. Due to their low cost and ease of handling, sodium, magnesium, and calcium salts are preferred. Furthermore, sodium salts are particularly preferred because they allow for easy adjustment of the balance of various properties.

[0042] In the pH-adjusted liquid composition, the proportion of 3HB salt is 10 per 100 moles of 3HB. It may be 0 moles or less, and can be selected from a range of about 0.1 to 100 moles, for example, 0.5 ~80 moles, preferably 1 to 60 moles, more preferably 3 to 50 moles, more 5 to 30 moles, most preferably 10 to 20 moles. These ratios (3HB 100 moles) The ratio of 3HB to the total ratio of 3HB and 3HB salts in the pH-adjusted liquid composition is... Even in a liquid composition where the proportion is 15% by mass or more (for example, 20-50% by mass), That's good. If the proportion of 3HB salt is too high, there is a risk of excessive salt intake in foods and medicines.

[0043] (Basic compounds) In the method of the present invention, the basic compound is a basic compound that can neutralize 3HB. The basic compound may be a basic inorganic compound or a basic organic compound. It may also be a compound.

[0044] Basic inorganic compounds include metal carbonates or metal bicarbonates, metal hydroxides, and metal fluorides. It contains substances, metal phosphates, metal borates, etc.

[0045] Examples of metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and sodium carbonate. Alkali metal carbonates such as calcium; alkaline earth minerals such as magnesium carbonate and calcium carbonate. Examples include metal carbonates.

[0046] Examples of metal bicarbonates include lithium bicarbonate, sodium bicarbonate, and hydrogen bicarbonate. Examples include potassium and alkali metal bicarbonates such as cesium bicarbonate.

[0047] Examples of metal hydroxides include lithium hydroxide, sodium hydroxide, and potassium hydroxide. alkali metal hydroxides such as cesium hydroxide; alkaline earth metal hydroxides such as barium hydroxide Examples include hydroxides.

[0048] Examples of metal fluorides include alkali metals such as potassium fluoride and cesium fluoride. Examples include fluorides.

[0049] Examples of metal phosphates include trisodium phosphate and tripotassium phosphate. Alkali metal phosphates; alkali metal hydrogen phosphates such as disodium hydrogen phosphate; dihydrate phosphate Examples include alkali metal dihydrogen phosphates such as sodium phosphate and potassium dihydrogen phosphate. ru.

[0050] Examples of metal borates include alkali metal borates such as sodium tetraborate (borax). Examples include uric acid salts.

[0051] Basic organic compounds include metal alkoxides, organic acid salts, basic amino acids or their salts, It contains alkylamines, alkanolamines, etc.

[0052] Examples of metal alkoxides include sodium methoxide, sodium ethoxide, and potassium alkoxide. Examples include alkali metal alkoxides such as t-butoxide.

[0053] Examples of organic acid salts include saturated monocarboxylic acid alkali metal salts such as sodium acetate. ;alkali metal salts of hydroxymonocarboxylic acids such as sodium lactate; trisodium malate Hydroxy, trisodium citrate, tripotassium citrate, disodium tartrate, etc. Alkali metal salts of polycarboxylates; disodium hydrogen citrate, dipotassium hydrogen citrate, etc. Which alkali metal hydroxypolycarboxylate hydrogen salts; sodium dihydrogen citrate, citrate Examples include alkali metal hydroxypolycarboxylate dihydrogen salts such as potassium dihydrogen acid. ru.

[0054] Basic amino acids include, for example, lysine, hydrolysine, arginine, histidine, Examples include ornithine, citrulline, and hydroxyzine. As salts of basic amino acids. For example, alkali metal salts such as sodium and potassium, and magnesium and calcium. Examples include various alkaline earth metal salts.

[0055] Examples of alkylamines include trimethylamine, triethylamine, and tributyl Examples include amines.

[0056] Examples of alkanolamines include ethanolamine, diethanolamine, and dimethylamine. Examples include chloroaminoethanol.

[0057] These basic compounds can be used individually or in combination of two or more. These salts The base compound is preferably a physiologically or pharmacologically acceptable compound.

[0058] Of these basic compounds, when 3HB is used in food or pharmaceuticals, excessive salt content Because their intake can be easily suppressed, metals such as potassium hydroxide and potassium citrate are used in potassium A basic compound that is mu is preferred.

[0059] Furthermore, among the basic compounds mentioned above, those with excellent handling properties are used as buffering agents and pH adjusters. Basic compounds with buffering properties are preferred, and salts used as buffering agents are preferred. Basic compounds are particularly preferred. Examples of basic compounds used as buffering agents include gold. Metal carbonates, metal bicarbonates, metal phosphates, borates, and organic acid salts are preferred, and tri-citric acid Alkali metal salts of hydroxypolycarboxylates such as sodium, disodium hydrogen citrate Alkali metal hydroxypolycarboxylates such as potassium dihydrogen citrate, etc. Dihydrogen dihydrogen hydroxypolycarboxylates of lucali metals are particularly preferred.

[0060] The ratio of basic compounds in the pH-adjusted liquid composition is the ratio of 3HB salt to 3HB. The ratio should be within the aforementioned range. In the liquid composition before pH adjustment, in the form of an acid The equivalent ratio of a basic compound to 3HB (basic compound / 3HB) is 0.1-50%. It can be selected from a range of degrees, for example 0.5 to 40%, preferably 1 to 35%, even more preferably pH is 3-30%, more preferably 5-25%, and most preferably 10-20%. In the liquid composition before preparation, the proportion of the basic compound is 50 parts by mass per 100 parts by mass of 3 HB. It may be less than or equal to parts by mass, and can be selected from a range of approximately 0.1 to 50 parts by mass, for example, 1 to 3 0 parts by mass, preferably 2 to 25 parts by mass, more preferably 3 to 20 parts by mass, even more preferably The amount is 5 to 15 parts by mass, most preferably 8 to 12 parts by mass. These proportions (3HB100 The ratio of 3HB to moles is the total ratio of 3HB and 3HB salts in the liquid mixture after pH adjustment. This is the proportion in a liquid composition that is 15% by mass or more (for example, 20-50% by mass) of the product. It is acceptable. If the proportion of basic compounds is too high, there is a risk of excessive salt intake in foods and medicines. There is.

[0061] (water) In the pH-adjusted liquid composition, the proportion of water is 10% by mass or more in the liquid composition. It is also possible to select from a range of approximately 10 to 99.9% by mass, for example, 30 to 99% by mass, preferred More preferably 50-98% by mass, more preferably 55-95% by mass, and more preferably 60-9% by mass. The mass percentage is 0%, most preferably 70-85%.

[0062] (Multimer) In the method of the present invention, the amount of 3HB can be suppressed, but if it is in trace amounts, the liquid after pH adjustment will remain. The composition may contain a polymer of 3HB. The polymer of B may be a polymer already present in the liquid composition before pH adjustment.

[0063] The average degree of polymerization of the 3HB oligomers should be 2 or higher, but for example, 2 to 10 Preferably 2 to 5, more preferably 2 to 4, more preferably 2 to 3, most preferably The answer is 2.

[0064] In the pH-adjusted liquid composition, the proportion of the 3HB polymer is determined by liquid chromatography. Based on the area ratio, for example, 10% or less of the total amount of 3HB and 3HB salt. It may be 5% or less, more preferably 4% or less, even more preferably The area percentage is 3% or less, most preferably 2% or less (for example, 0.1 to 2% area). Furthermore, it is more preferable that the pH-adjusted liquid composition substantially does not contain 3HB polymers. It is most preferable that the product contains absolutely no 3HB polymers.

[0065] In this specification and claims, the proportion of the 3HB polymer is defined as liquid chromatograph. Measurements can be taken based on tography, and more specifically, by the method described in the examples below. .

[0066] (oils and fats) The liquid composition may further contain oils and fats in addition to 3HB and water. It may be vegetable oil, animal oil, or processed oil.

[0067] Examples of vegetable oils include soybean oil, cottonseed oil, linseed oil, castor oil, safflower oil, and rice bran oil. Brown rice oil, corn oil, sesame oil, sunflower oil, rice bran oil, rapeseed oil such as canola oil, peanut oil , vegetable oils such as palm kernel oil, olive oil, and grapeseed oil (salad oil, refined oil); coconut Examples include oils, palm oil such as carotino oil, and vegetable oils (vegetable fats) such as cocoa butter. .

[0068] Examples of animal fats include butter, beef tallow, milk fat, lard, and fish oil. Food fats are one example.

[0069] Examples of processed oils include margarine, shortening, coconut milk, and C 8- 10 Examples include medium-chain triglycerides (MCTs), such as fatty acid triglycerides. .

[0070] These oils and fats may be fractionated oils, transesterified oils, or hydrogenated oils. These fats and oils may be in solid or liquid form, and may have a specific crystalline form (e.g. For example, it may contain beta-type fats.

[0071] In the pH-adjusted liquid composition, the proportion of oils and fats is 10% of the total of 3HB and 3HB salt. For example, the amount may be 50 parts by mass or less, preferably 30 parts by mass or less, relative to 0 parts by mass. More preferably 20 parts by mass or less, more preferably 10 parts by mass or less, and most preferably 5 parts by mass or less. It is less than or equal to parts. Since the liquid composition is an aqueous composition containing water, it substantially contains oils and fats. It is not strictly necessary, and it is especially preferable that it contains no oils or fats at all.

[0072] (Other ingredients) The liquid composition, in addition to 3HB and water, contains other ingredients, such as liquid compositions for food and pharmaceuticals. It may also contain other ingredients that are included in the formulation.

[0073] Other ingredients include, for example, sugars, sweeteners, acidulants, amino acids, flavorings, surfactants, and milk. Fueling agents, proteins, ketone esters, dietary fiber, colorings, seasonings, leavening agents or foaming agents Examples include thickening and stabilizing agents or water-retaining emulsifying stabilizers, preservatives, and defoaming agents.

[0074] Examples of sugars include pentoses such as arabinose and xylose; glucose (glucose) Hexosaccharides such as coagulant, fructose, galactose, mannose, and sorbose. Rare sugars such as cereals and psicose, monosaccharides such as honey; sucrose (for example, white sugar and refined white sugar) Sugars (powdered sugar, granulated sugar, cane sugar, brown sugar, light brown sugar, etc.), lactose, isomerized milk Two types of sugars such as lactulose, maltose, isomaltose, and trehalose. Sugars; maltotriose, isomalttriose, panose, starch hydrolysates (dextrin) Oligosaccharides such as (oligosaccharides with three or more saccharides); xylitol, erythritol, sorbitol Mannitol, reduced maltose syrup (maltitol), reduced starch syrup, reduced palatinose Examples include sugar alcohols such as reduced lactose (lactitol).

[0075] Examples of sweeteners (non-sugar sweeteners) include natural sweeteners such as stevia, licorice, and hydrangea. Sweeteners: Saccharin, sodium saccharin, aspartame, acesulfame potassium Examples include artificial sweeteners such as sucralose and neotame.

[0076] Examples of acidulants include saturated monocarboxylic acids such as acetic acid; malonic acid, succinic acid, and anhydride. Saturated dicarboxylic acids such as succinic acid and glutaric acid; unsaturated polycarboxylic acids such as maleic acid and fumaric acid. Carboxylic acids; hydroxymonocarboxylic acids such as lactic acid; malic acid, tartaric acid, citric acid, etc. Hydroxypolycarboxylic acids; examples include ascorbic acid and gluconic acid.

[0077] Examples of amino acids include glycine, alanine, valine, isoleucine, proline, Neutral amino acids such as methionine, tryptophan, tyrosine, and glutamine; asparagine Examples include acids and acidic amino acids such as glutamic acid.

[0078] The fragrance may be a natural fragrance or a synthetic fragrance.

[0079] Examples of natural flavorings include strawberry, blueberry, apple, plum, and orange. Fruit essences or oils such as lemon, lime, vanilla, and pepper; orange, holo Fruit peel essences or oils such as white grape, grapefruit, and lemon; Bark-based essences or oils such as cinnamon; bark-based powders such as cinnamon powder. Udah; root vegetable essences or oils such as ginger; roots such as ginger powder Vegetable powders; seed powders such as vanilla beans and cocoa powder; peppermint, spearmint Mint, rosemary, and other leafy essences or oils; peppermint powder, etc. Powders of branches and leaves; such as jasmine, lavender, rose, rosemary, and hyacinth. Examples include floral essences or oils.

[0080] Examples of synthetic fragrances include benzyl acetate, linalyl acetate, citral, and citronellal. Examples include citronellol, cis-jasmine, cis-3-hexenol, and menthol. It is possible.

[0081] Examples of surfactants include sodium lauryl sulfate, polysorbate 80, and polio Examples include xyethylene(160) polyoxypropylene(30) glycol.

[0082] Examples of emulsifiers include phospholipids, sucrose fatty acid esters, and glycerol fatty acid esters. Sters, sorbitan fatty acid esters, propylene glycol fatty acid esters, etc. It can be listed.

[0083] Examples of protein sources include whey protein, casein protein, and soy protein. Soy protein, pea protein, wheat protein, egg protein, Examples include isoprotein.

[0084] Examples of ketone esters include the ketone ester of 3HB and 1,3-butanediol. Examples include Teru.

[0085] Examples of vitamins include vitamin A, vitamin D, vitamin E, vitamin B1, Vitamin B2, Vitamin B6, Vitamin C, Vitamin B 12 These are some examples.

[0086] Examples of dietary fiber include wheat bran, corn bran, oat bran, and corn fiber. Bar, soy fiber, beet fiber, acacia fiber, crystalline cellulose, indigestible Examples include dextrin, agar, chitosan, chitin, hemicellulose, lignin, and glucan. It can be done.

[0087] Examples of colorants include food colorings such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2. Examples include edible lake pigments and red iron oxide.

[0088] Examples of seasonings include salt, vinegar, soy sauce, fish sauce, mirin, cooking sake, miso, sauce, and powder. Dashi (dried sardine broth, kelp broth, bonito broth, etc.), bonito flakes, Western-style broth (consommé, mirepoix, broth) (e.g., oyster sauce), spices (garlic, ginger, cloves, cumin, sansho pepper, myoga ginger, Examples include pepper, chili peppers, etc.

[0089] Examples of leavening agents or foaming agents include baking soda.

[0090] Examples of thickening and stabilizing agents or water-retaining emulsifying stabilizers include pectin, cellulose, and other thickening agents. Examples include polysaccharides.

[0091] Examples of preservatives include antimicrobial agents, antibacterial agents, antioxidants, and light stabilizers.

[0092] Examples of defoaming agents include silicone-based defoaming agents.

[0093] These other ingredients can be used individually or in combination of two or more. (pH-adjusted liquid) In the composition, the proportion of these other components is 100 parts by mass of 3HB and 3HB salt combined. In contrast, for example, it may be 100 parts by mass or less, preferably 50 parts by mass or less, and even more preferably More preferably 30 parts by mass or less, more preferably 20 parts by mass or less, and most preferably 10 parts by mass or less It is below (for example, 0.1 to 10 parts by mass).

[0094] [Liquid composition] The liquid composition stabilized by the method of the present invention comprises 3HB and water, and is in the form of a free acid. Despite containing a certain amount of 3HB, the increase in 3HB can be suppressed. For example, the present invention This not only suppresses the increase in 3HB even when the liquid composition is stored for a long period of time in a refrigerator, but also Furthermore, even when stored at high temperatures of around 60°C, the increase in 3HB can be suppressed.

[0095] (First liquid composition) The liquid composition stabilized by the method of the present invention contains 3HB and water, and has a pH of 2 or higher. It may be a liquid composition (first liquid composition) which is 3HB It is sufficient that it contains pre-treatment water, and the pH of the first liquid composition is preferably 2.2 or higher. It can be selected from a range of approximately ~7, for example 2.3 to 6, preferably 2.4 to 5.5, and even more preferably The ratio is 2.5 to 5, more preferably 3 to 4.5, and most preferably 3.3 to 4. The liquid composition 1 may or may not contain the 3HB salt.

[0096] In the first liquid composition, the total proportion of 3HB and 3HB salt is such that 3HB is in its free form. In terms of HB, it may be 0.1% by mass or more in the first liquid composition, for example, 0.1 to 70 Mass%, preferably 1 to 60% by mass, more preferably 2 to 55% by mass, more The amount is 3 to 50% by mass, most preferably 5 to 45% by mass.

[0097] The first liquid composition, in addition to 3HB and water, contains other ingredients such as liquid food and pharmaceutical ingredients. The composition may further contain components that are incorporated into the composition. Other components include the liquid composition. Other components are exemplified in the section on stabilization methods. The proportion of other components is 3HB For a total of 100 parts by mass of the 3HB salt, the amount may be, for example, 100 parts by mass or less. More preferably 50 parts by mass or less, more preferably 30 parts by mass or less, and more preferably 20 parts by mass Hereafter, the most preferred amount is 10 parts by mass or less (for example, 0.1 to 10 parts by mass).

[0098] (Second liquid composition) In the method of the present invention, the liquid composition stabilized using the partial neutralization method (second liquid composition The substance contains 3HB, 3HB salt, and water. In this liquid composition, the proportion of 3HB salt is It may be 100 moles or less per 100 moles of 3HB, and approximately 0.1 to 100 moles. The range can be selected, for example, 0.5 to 80 moles, preferably 1 to 60 moles, and more preferably The amount is 3 to 50 moles, more preferably 5 to 30 moles, and most preferably 10 to 20 moles. These ratios (the ratio of 3HB salt to 100 moles of 3HB) are for 3HB and 3HB salt. The total proportion is 15% by mass or more (e.g., 20-50% by mass) of the liquid composition after pH adjustment. The proportion may be in the liquid composition.

[0099] In the second liquid composition, the total proportion of 3HB and 3HB salt is 3 in free form. The amount may be adjusted to 15% by mass or more (especially 20% by mass or more) in the second liquid composition, in terms of HB. For example, 15-70% by mass, preferably 20-60% by mass, and more preferably 25-5% by mass. The amount is 5% by mass, more preferably 30-50% by mass, and most preferably 35-45% by mass.

[0100] In the second liquid composition, the proportion of water is 10% by mass or more in the second liquid composition. It is also possible to select from a range of approximately 10 to 99.9% by mass, for example, 30 to 99% by mass, preferred More preferably 50-98% by mass, more preferably 55-95% by mass, and more preferably 60-9% by mass. The mass percentage is 0%, most preferably 70-85%.

[0101] The second liquid composition, in addition to 3HB, 3HB salt, and water, contains other ingredients such as food and medicine The liquid composition of the drug may further contain components. Other components include the aforementioned Other components exemplified in the section on methods for stabilizing liquid compositions include the proportions of the other components. For example, 100 parts by mass or less per 100 parts by mass of 3HB and 3HB salt in total. This is also acceptable, preferably 50 parts by mass or less, more preferably 30 parts by mass or less, more preferably The amount is 20 parts by mass or less, most preferably 10 parts by mass or less (for example, 0.1 to 10 parts by mass).

[0102] The pH of the second liquid composition is preferably 2.2 or higher, and can be selected from a range of approximately 2.2 to 7. For example, 2.3 to 6, preferably 2.4 to 5.5, even more preferably 2.5 to 5, more Preferably, it is 3 to 4.5, most preferably 3.3 to 4.

[0103] (Third liquid composition) In the method of the present invention, the stabilized product is obtained using only the concentration adjustment method, without using the partial neutralization method. The liquid composition (third liquid composition) is a liquid containing 3HB and water, but not containing the 3HB salt. It may also be a crystalline composition.

[0104] In the third liquid composition, the proportion of 3HB is less than 15% by mass of the third liquid composition. It may be, for example, 0.1 to 14% by mass, preferably 1 to 13% by mass, and even more preferably The amount is 2 to 12% by mass, more preferably 3 to 11% by mass, and most preferably 5 to 10% by mass. .

[0105] In the third liquid composition, the proportion of water is 80% by mass or more in the third liquid composition. Also, for example, 80-99% by mass, preferably 85-98% by mass, and more preferably 90% It is approximately 95% by mass.

[0106] The third liquid composition, in addition to 3HB and water, contains other ingredients such as liquid food or pharmaceutical ingredients. The composition may further contain components that are incorporated into the composition. Other components include the liquid composition. Other components exemplified in the section on stabilization methods include 3HB1. For every 00 parts by mass, the amount may be, for example, 100 parts by mass or less, preferably 50 parts by mass or less. More preferably 30 parts by mass or less, more preferably 20 parts by mass or less, most preferably It is 10 parts by mass or less (for example, 0.1 to 10 parts by mass).

[0107] The pH of the third liquid composition is preferably 2.2 or higher, and can be selected from a range of approximately 2.2 to 5. For example, 2.2 to 4, preferably 2.2 to 3, even more preferably 2.2 to 2.5, more Preferably, it is 2.2 to 2.4.

[0108] [Application] The liquid composition stabilized by the method of the present invention can be used in the fields of food and pharmaceuticals, and can be used as is. It may be used as a liquid composition (liquid preparation) for food or pharmaceuticals. For example, drinks, suspensions, emulsions, syrups, injections, liquid syrups, etc. Examples include bucks, etc. Furthermore, liquid compositions such as beverages, whether undiluted or concentrated, Good. The liquid composition may be packed or packaged in a conventional manner. However, it is not limited to the above. The liquid composition may undergo heat treatment, etc., before or after packing. Sterilization may be performed by a specific method.

[0109] Furthermore, the liquid composition stabilized by the method of the present invention is a semi-solid composition used as a food or pharmaceutical. It may also be used as a raw material for a finished product (semi-solid agent) or a solid composition (solid agent).

[0110] Examples of semi-solid compositions (semi-solid preparations) include gels, creams, jellies, and slurry. Examples include pastes, sherbets, etc. The semi-solid composition is the stable liquid composition. It may also contain other components, such as thickeners, as exemplified in the section on the method of standardization.

[0111] Examples of thickening agents include agar, carrageenan, alginic acid, pectin, and xanthan gum. Polysaccharides such as gum, locust bean gum, curdlan, carboxymethylcellulose, and ze Gelling agents such as latin and other proteins; gluten derived from wheat flour (gliadin and gluten) A complex with (a type of fish protein (myofibrillar protein)) to form the base of processed seafood products. Examples include quality, etc. These thickeners can be used alone or in combination of two or more types. Of these, gelatin, gluten, and fish protein are preferred. (Proportion of thickener) This can be selected from a range of approximately 1 to 50% by mass relative to the total amount of the semi-solid preparation, for example, 2 to 40% by mass. The amount is %, preferably 3 to 30% by mass, and more preferably 5 to 20% by mass.

[0112] The semi-solid composition may be packed or packaged in a conventional manner. However, it is not limited to the above. The semi-solid composition may undergo heat treatment before or after packing. Sterilization may be performed by methods such as those listed above.

[0113] Examples of solid compositions (solid preparations) include pellets, powders, fine granules, granules, and pills. Tablets such as sugar-coated tablets, flakes, cakes, gummies, nougat, film formulations, capsules Examples include agents. Examples of solid compositions are those exemplified in the section on methods for stabilizing liquid compositions. It may further contain the following components, excipients, binders, disintegrants, lubricants, etc.

[0114] The excipient may be an organic excipient or an inorganic excipient. Examples of organic excipients include For example, crystalline cellulose; mannitol, sorbitol, xylitol, maltitol, etc. Sugar alcohols such as lysritol, lactitol, and reduced starch syrup, lactose (anhydrous lactose, lactose water) Sugars (monosaccharides or disaccharides) such as sucrose, glucose, fructose, and maltose (including Japanese sugars); Ligosaccharides, corn starch, potato starch, wheat starch, partially pregelatinized starch Examples include pregelatinized starch and other starches (or polysaccharides). Inorganic excipients Examples of agents include light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, and anhydrous calcium phosphate. Examples include calcium silicate and calcium carbonate. These excipients can be used alone. Or, two or more types can be used in combination. Among these, crystalline cellulose, sugars (sugar alcohols) (Lithium, monosaccharides and disaccharides), light anhydrous silicic acid, anhydrous calcium hydrogen phosphate. The proportion of the binder can be selected from a range of approximately 0.01 to 90% by mass in the solid dosage form, and from 0.05 to 8%. The amount is 0% by mass, preferably 0.1 to 70% by mass, and more preferably 0.5 to 60% by mass. .

[0115] Examples of binders include hydroxypropyl cellulose (HPC) and hydroxypropyl Pyromethylcellulose (HPMC), Methylcellulose (MC), Carboxymethylcellulose Cellulose ethers such as CMC-Na and carboxymethylcellulose sodium. Examples include carboxymethyl starch, pregelatinized starch, partially pregelatinized starch, etc. Soluble starch; dextrin, pullulan, acacia gum, tragacanth, sodium alginate Polysaccharides such as um, agar, and gelatin; povidone (polyvinylpyrrolidone), copribit Don, carboxyvinyl polymer, polyacrylic acid polymer, polylactic acid, polyvinyl Examples include synthetic polymers such as ethanol and polyethylene glycol. These can be used alone or in combination of two or more. Among these, HPMC, Carmelo -Sodium and povidone are preferred. The proportion of the binder should be 0.5 to 20% by mass in the solid dosage form. Preferably, it is 1 to 15% by mass, and more preferably 2 to 10% by mass.

[0116] Examples of disintegrants include corn starch, hydroxypropyl starch, and carboxymethyl Methyl starch sodium, carmellose, carmellose sodium, carmellose car Cium, croscarmellose sodium, crospovidone (cross-linked polyvinylpyrrolidone) Examples include low-substituted hydroxypropyl cellulose (L-HPC). Destructor can be used alone or in combination of two or more. Of these, carboxymeth Lustacean sodium, carmellose calcium, croscarmellose sodium, chloro Spovidone is preferred. The proportion of the disintegrant is 0.5 to 25% by mass in the solid dosage form, preferably 1 It is approximately 20% by mass, more preferably 2 to 15% by mass.

[0117] Examples of lubricants include stearic acid, magnesium stearate, and stearate. Calcium, sucrose fatty acid ester, talc, waxes, sodium lauryl sulfate, lauryl Examples include magnesium lyl sulfate and macrogol 6000. These lubricants are simple It can be used individually or in combination of two or more types. Of these, magnesium stearate Which fatty acid metal salt is preferred? The proportion of the lubricant should be 0.1 to 10% in the solid dosage form (especially tablets). The amount is in mass%, preferably 0.2 to 5 mass%, and more preferably 0.3 to 2 mass%.

[0118] Solid compositions may be packed or wrapped in conventional methods. Even if there are any, they are not particularly limited. The solid composition may undergo heat treatment, etc., before or after packing. Sterilization may be performed by a specific method.

[0119] Furthermore, the solid composition may be used as a raw material for the liquid composition stabilized by the method of the present invention. good.

[0120] Furthermore, the liquid composition stabilized by the method of the present invention is taken orally as a food or pharmaceutical. At that time, the pH may be further adjusted within any range depending on the application. Salt intake and shelf life From this perspective, a lower pH is preferable, but for example, weakly acidic or medium-acid substances such as tea and coffee are preferable. When using it in beverages with a similar pH, it is preferable to adjust the pH to around 5-7. In particular, in the pH range of 5.5 to 6.5, a liquid composition containing 3HB is a single acid The characteristic sourness, bitterness, and saltiness of salt disappear, and it can be consumed even without the addition of sweeteners or flavorings. It becomes easier. Furthermore, in liquid compositions containing the sodium salt of 3HB, the pH is 6.1 ± 0.1. Preferably, in liquid compositions containing the calcium salt of 3HB, the pH is preferably 6.25 ± 0.1. In liquid compositions containing the magnesium salt of 3HB, a pH of 6.05±0.1 is preferred. In liquid compositions containing potassium salts of B, a pH of 6.0 ± 0.1 is preferred. These salts alone It may be used as is, or two or more may be used in combination, and from the perspective of salt intake, it is less It is preferable that it contains 3HB, which is in the form of an acid. As for methods of adjusting the pH, for example, In addition to the method of adding the basic compound, there is a method of adding at least one 3HB salt. Methods include dilution with water. Furthermore, when ingesting a liquid composition containing 3HB, By adding a basic compound or at least one 3HB salt, half It may be taken in solid form or prepared in solid form. Furthermore, it may be taken in semi-solid or solid form. When taking the product, the semi-solid or solid composition may be dissolved in water before ingestion. [Examples]

[0121] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. Therefore, it is not limited to the raw materials used in the examples and the liquid mixture prepared in the examples. The method for evaluating the storage stability of the finished product is as follows:

[0122] [Raw materials] Crystalline (R)3HB: (R)3HB [Osaka Gas Chemical Co., Ltd. "OKETOA (Registered) (Trademark), acid form: Add distilled water to prepare a 20% by mass concentration, and freeze completely at -40°C. Crystalline (R)3HB obtained by crystallizing the material using a freeze-dryer.

[0123] Trisodium citrate: Manufactured by Kishida Chemical Co., Ltd., anhydrous trisodium citrate.

[0124] [Storage stability (dimer content)] The dimer content was measured using high-performance liquid chromatography (HPLC) under the following conditions. did.

[0125] Equipment: Chromaster manufactured by Hitachi High-Tech Science Corporation Column: Metacarb 67H manufactured by Agilent Technologies, Inc. Mobile phase: 5mM H2SO4 aqueous solution Detector: RI Flow rate: 0.8mL / min.

[0126] (1) Investigation of the concentration of (R)3HB Example 1 (10% in Figure 1) Add 1.0g of crystalline (R)3HB to 9.0g of distilled water and stir with a magnetic stirrer. Stirring was performed to prepare an aqueous solution with a concentration of 10% by mass of 3HB. The resulting aqueous solution was sealed in a vial. The aqueous solution was heated at 60°C for 70 days, and its storage stability was evaluated over time.

[0127] Reference Example 1 (20% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 20% by mass. Sexuality was evaluated over time.

[0128] Reference Example 2 (30% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 30% by mass. Sexuality was evaluated over time.

[0129] Reference Example 3 (40% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 40% by mass. Sexuality was evaluated over time.

[0130] Reference Example 4 (50% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 50% by mass. Sexuality was evaluated over time.

[0131] Reference Example 5 (60% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 60% by mass. Sexuality was evaluated over time.

[0132] Reference Example 6 (70% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 70% by mass. Sexuality was evaluated over time.

[0133] Reference Example 7 (80% in Figure 1) Storage stability of the aqueous solution is obtained in the same manner as in Example 1, except that the concentration of 3HB is changed to 80% by mass. Sexuality was evaluated over time.

[0134] The evaluation results of the aqueous solutions obtained in Example 1 and Reference Examples 1-7 are shown in Figure 1.

[0135] As is clear from Figure 1, the aqueous solution of Example 1 still contains dimers even after heating for 70 days. The quantity remained unchanged and the storage stability was excellent. On the other hand, in the aqueous solutions of Reference Examples 1-7, all Dimers are formed upon heating, and the higher the concentration of crystalline (R)3HB, the higher the dimer content. There was a tendency for the quantity to be large.

[0136] (2) Examination of the presence or absence of KOH Reference example 8 Add 2.0g of crystalline (R)3HB to 8.0g of distilled water and stir with a magnetic stirrer. The mixture was stirred to prepare an aqueous solution with a concentration of 20% by mass of 3HB. The resulting aqueous solution was sealed in a vial. After heating at 60°C for 4 weeks, the storage stability of the aqueous solution was evaluated, and the proportion of dimers was 3H It represented 4.4% of area relative to B.

[0137] Reference example 9 Except for changing the concentration of 3HB to 40% by mass, the storage stability of the aqueous solution is the same as in Reference Example 8. Based on the evaluation of the properties, the proportion of dimers was 12.9% of the area relative to 3HB.

[0138] Reference example 10 Except for changing the concentration of 3HB to 50% by mass, the storage stability of the aqueous solution is the same as in Reference Example 8. Based on the evaluation of the properties, the proportion of dimers was found to be 21.0 area% relative to 3HB.

[0139] Example 2 Add 2.0g of crystalline (R)3HB to 8.0g of distilled water and stir with a magnetic stirrer. Stirring to prepare an aqueous solution with a 3HB concentration of 20% by mass, and then adding KOH to obtain the aqueous solution The pH of the solution was adjusted to 4. The obtained aqueous solution with pH 4 was sealed in a vial and heated at 60°C for 4 weeks After heating, as a result of evaluating the storage stability of the aqueous solution, the presence of dimers could not be confirmed .

[0140] Example 3 4.0 g of crystalline (R)-3HB was added to 6.0 g of distilled water and stirred with a magnetic stirrer to prepare an aqueous solution with a 3HB concentration of 40% by mass. Further, KOH was added to adjust the pH of the obtained aqueous solution to 4. The obtained aqueous solution with pH 4 was sealed in a vial and heated at 60°C for 4 weeks After heating, as a result of evaluating the storage stability of the aqueous solution, the proportion of dimers was 4.7 area% with respect to the total amount converted to 3HB in the form in which the total of 3HB and 3HB salt was free .

[0141] Example 4 5.0 g of crystalline (R)-3HB was added to 5.0 g of distilled water and stirred with a magnetic stirrer to prepare an aqueous solution with a 3HB concentration of 50% by mass. Further, KOH was added to adjust the pH of the obtained aqueous solution to 4. The obtained aqueous solution with pH 4 was sealed in a vial and heated at 60°C for 4 weeks After heating, as a result of evaluating the storage stability of the aqueous solution, the proportion of dimers was 8.6 area% with respect to the total amount converted to 3HB in the form in which the total of 3HB and 3HB salt was free .

[0142] The evaluation results of the aqueous solutions obtained in Reference Examples 8 to 10 and Examples 2 to 4 are shown in Table 1

[0143]

Table 1

[0144] As is clear from the results in Table 1, in the aqueous solutions of Examples 2 to 4, 3HB was 20% by mass or more​​​​ Even if it contains KOH, the presence of KOH results in a different dimer formation compared to the aqueous solutions in Reference Examples 8-10. The growth was suppressed.

[0145] (3) Investigation of pH of 3HB5 mass% aqueous solution Example 5 (No adjustments made in Figure 2) Add 2.5g of crystalline (R)3HB to 47.5g of distilled water and stir with a magnetic stirrer. The mixture was stirred to prepare an aqueous solution with a concentration of 5% by mass of 3HB. The pH of the resulting aqueous solution was 2.3. The resulting pH 2.3 aqueous solution was sealed in a vial and heated at 60°C for one week, and then... The storage stability of the aqueous solution was evaluated.

[0146] Example 6 (pH 2.5 in Figure 2) Add 2.5g of crystalline (R)3HB to 47.5g of distilled water and stir with a magnetic stirrer. Stirring with 3HB to prepare an aqueous solution with a concentration of 5% by mass, and then add 0.00% trisodium citrate. The pH of the aqueous solution obtained by adding 1 g was adjusted to 2.5. The aqueous solution was sealed in a vial and heated at 60°C for one week, after which its storage stability was evaluated.

[0147] Example 7 (pH 3.0 in Figure 2) The amount of trisodium citrate added was changed to 0.069g to adjust the pH of the aqueous solution to 3.0. The storage stability of the aqueous solution was evaluated in the same manner as in Example 6, except for the following:

[0148] Example 8 (pH 3.5 in Figure 2) The amount of trisodium citrate added was changed to 0.313g to adjust the pH of the aqueous solution to 3.5. The storage stability of the aqueous solution was evaluated in the same manner as in Example 6, except for the following:

[0149] Example 9 (pH 4.0 in Figure 2) Change the addition amount of trisodium citrate to 0.738 g and adjust the pH of the aqueous solution to 4.0 Except for this, the storage stability of the aqueous solution was evaluated in the same manner as in Example 6.

[0150] (4) Examination regarding the pH of a 10 mass% aqueous solution of 3HB Example 10 (without adjustment in FIG. 3) Add 5.0 g of 3HB to 45.0 g of distilled water and stir with a magnetic stirrer for 3 An aqueous solution with a 3HB concentration of 10 mass% was prepared. The pH of the obtained aqueous solution was 2.2. The obtained aqueous solution with a pH of 2.2 was sealed in a vial and heated at 60 °C for 1 week, and then the storage stability of the aqueous solution was evaluated.

[0151] Example 11 (pH 2.5 in FIG. 3) Add 5.0 g of crystalline (R)-3HB to 45.0 g of distilled water and stir with a magnetic stirrer to prepare an aqueous solution with a 3HB concentration of 10 mass%. Further, add 0.0 45 g of trisodium citrate to adjust the pH of the obtained aqueous solution to 2.5. The obtained aqueous solution with a pH of 2.5 was sealed in a vial and heated at 60 °C for 1 week, and then the storage stability of the aqueous solution was evaluated .

[0152] Example 12 (pH 3.0 in FIG. 3) Change the addition amount of trisodium citrate to 0.177 g and adjust the pH of the aqueous solution to 3.0 Except for this, the storage stability of the aqueous solution was evaluated in the same manner as in Example 11.

[0153] Example 13 (pH 3.5 in FIG. 3) Change the addition amount of trisodium citrate to 0.501 g and adjust the pH of the aqueous solution to 3.5 Except for this, the storage stability of the aqueous solution was evaluated in the same manner as in Example 11.

[0154] Example 14 (pH 4.0 in FIG. 3) The amount of trisodium citrate added was changed to 1.542g to adjust the pH of the aqueous solution to 4.0. The storage stability of the aqueous solution was evaluated in the same manner as in Example 11, except for the following:

[0155] (5) Investigation of pH of 20% by mass aqueous solution of 3HB Reference Example 11 (No adjustments made in Figure 4) Add 10.0g of crystalline (R)3HB to 40.0g of distilled water and use a magnetic stirrer. The mixture was stirred to prepare an aqueous solution with a concentration of 20% by mass of 3HB. The pH of the resulting aqueous solution was 2.1 The resulting pH 2.1 aqueous solution was sealed in a vial and heated at 60°C for one week. The storage stability of the aqueous solution was then evaluated.

[0156] Example 15 (pH 2.5 in Figure 4) Add 10.0g of crystalline (R)3HB to 40.0g of distilled water and use a magnetic stirrer. Stirring with - to prepare an aqueous solution of 3HB with a concentration of 20% by mass, and then add 0.5% trisodium citrate. The pH of the aqueous solution obtained by adding 0.94g was adjusted to 2.5. The solution was sealed in a vial and heated at 60°C for one week, after which the storage stability of the aqueous solution was evaluated. Ta.

[0157] Example 16 (pH 3.0 in Figure 4) The amount of trisodium citrate added was changed to 0.293g to adjust the pH of the aqueous solution to 3.0. The storage stability of the aqueous solution was evaluated in the same manner as in Example 15, except for the following:

[0158] Example 17 (pH 3.5 in Figure 4) The amount of trisodium citrate added was changed to 1.133g to adjust the pH of the aqueous solution to 3.5. The storage stability of the aqueous solution was evaluated in the same manner as in Example 15, except for the following:

[0159] Example 18 (pH 4.0 in Figure 4) The amount of trisodium citrate added was changed to 2.789g to adjust the pH of the aqueous solution to 4.0. The storage stability of the aqueous solution was evaluated in the same manner as in Example 15, except for the following:

[0160] (6) Investigation of pH of 40% by mass aqueous solution of 3HB Reference Example 12 (No adjustments made in Figure 5) Add 20.0g of crystalline (R)3HB to 30.0g of distilled water and use a magnetic stirrer. The mixture was stirred to prepare an aqueous solution with a 3HB concentration of 40% by mass. The pH of the resulting aqueous solution was 1.7 The obtained pH 1.7 aqueous solution was sealed in a vial and heated at 60°C for one week. The storage stability of the aqueous solution was then evaluated.

[0161] Example 19 (pH 2.5 in Figure 5) Add 20.0g of crystalline (R)3HB to 30.0g of distilled water and use a magnetic stirrer. Stirring with - to prepare an aqueous solution of 3HB with a concentration of 40% by mass, and then add 0.5% trisodium citrate. The pH of the aqueous solution obtained by adding 220g was adjusted to 2.5. The solution was sealed in a vial and heated at 60°C for one week, after which the storage stability of the aqueous solution was evaluated. Ta.

[0162] Example 20 (pH 3.0 in Figure 5) The amount of trisodium citrate added was changed to 0.632g to adjust the pH of the aqueous solution to 3.0. The storage stability of the aqueous solution was evaluated in the same manner as in Example 19, except for the following:

[0163] Example 21 (pH 3.5 in Figure 5) The amount of trisodium citrate added was changed to 1.907g to adjust the pH of the aqueous solution to 3.5. The storage stability of the aqueous solution was evaluated in the same manner as in Example 19, except for the following:

[0164] Example 22 (pH 4.0 in Figure 5) The amount of trisodium citrate added was changed to 4.714g to adjust the pH of the aqueous solution to 4.0. The storage stability of the aqueous solution was evaluated in the same manner as in Example 19, except for the following:

[0165] The aqueous solutions obtained in Examples 5-9, the aqueous solutions obtained in Examples 10-14, and Reference Example 11 The aqueous solutions obtained in Examples 15-18, and the water obtained in Reference Example 12 and Examples 19-22. The evaluation results of the solutions are shown in Figures 2 to 5.

[0166] From the results in Figures 2 and 3, in aqueous solutions with 3HB concentrations of 5% by mass and 10% by mass, The dimer content ratio was found to be independent of pH and approximately 2% by mass. Since the aqueous solution originally contains approximately 2% by mass of dimers relative to the 3HB monomer, It is thought that dimerization does not proceed significantly within the concentration range.

[0167] On the other hand, from the results in Figures 4 and 5, aqueous solutions with 3HB concentrations of 20% by mass and 40% by mass were obtained. In this case, compared to an aqueous solution that has not undergone pH adjustment, an aqueous solution whose pH has been adjusted to 2.5 or higher is superior. It was found that the dimer content ratio was clearly low. Also, the pH was in the range of 2.5 to 4.0. In this case, no clear difference was observed between the unadjusted solution and the solution with a pH of 2.5. Therefore, 3HB has buffering capacity in the concentration range of 10% by mass or more, trisodium citrate It has become clear that adding small amounts of um (a specific substance) significantly improves storage stability. . [Industrial applicability]

[0168] The liquid composition of the present invention is a beverage or its concentrate used in the fields of food and pharmaceuticals. It can be used as a concentrated liquid, and is also useful as a raw material for semi-solid or solid foods and pharmaceuticals. It can be used.

Claims

1. A liquid composition comprising 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid, and water.

2. The liquid composition according to claim 1, wherein the proportion of the salt of 3-hydroxybutyric acid is 0.1 to 100 moles per 100 moles of 3-hydroxybutyric acid.

3. The liquid composition according to claim 1 or 2, wherein the total proportion of the 3-hydroxybutyric acid and the salt of the 3-hydroxybutyric acid is 15% by mass or more in the liquid composition, in terms of 3-hydroxybutyric acid in its free form.

4. The liquid composition according to claim 1 or 2, wherein the 3-hydroxybutyric acid is R-3-hydroxybutyric acid produced by fermentation using microorganisms, and the pH of the liquid composition is 2.2 or higher.

5. A liquid composition according to claim 1 or 2, which is a beverage or its concentrate.

6. A liquid composition comprising 3-hydroxybutyric acid and water, and having a pH of 2 or higher.

7. The liquid composition according to claim 6, which does not contain a salt of 3-hydroxybutyric acid and has a pH of 2.2 or higher.

Images