Complex of 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate and method for preparing same

Abstract

The present invention provides a complex comprising 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate. [Solution] The ratio of 3-hydroxybutanoic acid to sodium 3-hydroxybutanoate is 1:10 to 10:1. The preparation method includes: (1) obtaining substance A by one of the following methods: mixing 3-hydroxybutanoic acid with sodium 3-hydroxybutanoate; adding 3-hydroxybutanoic acid to an aqueous solution of an alkaline sodium compound, stirring to remove water, and steaming until nearly dry; or reacting alkyl 3-hydroxybutanoate with water by heating in the presence of a catalyst, cooling, filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and steaming until nearly dry; (2) adding one or more solvents selected from water, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAC), alcohols, halogenated hydrocarbons, ketones, and esters to substance A obtained in step (1); stirring and cooling to precipitate a solid; and (3) filtering and drying the solid to obtain the complex. The above complexes are applied to the preparation of ketogenic substances for increasing or maintaining blood ketone levels in test subjects.

Description

[Technical Field]

[0001] The present invention belongs to the technical field of dietary or nutritional supplements, and specifically relates to a complex of 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate and a method for preparing the same. [Background technology]

[0002] Currently, people are increasingly turning to dietary or nutritional supplements to improve their personal health and reduce the risk of disease, and athletes are also using them to improve muscle strength and performance.

[0003] Normally, the human body relies on glucose for energy. However, when glucose supplies are insufficient to meet the body's energy needs, such as during prolonged exercise, starvation, or periods of dietary carbohydrate deprivation, the body shifts to burning fat for fuel. Because the brain and central nervous system cannot directly utilize fat for energy, the liver produces ketone bodies from fatty acids as an alternative fuel, which are released into the blood / plasma. Ketone bodies not only fuel the brain but are also used by skeletal and cardiac muscles. Ketone body metabolism has been associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle-sparing properties, and improved cognitive and physical performance. Science-based improvements in the efficiency of cellular metabolism, managed through ketone supplementation, have beneficial effects on physical, cognitive, and psychological health and may have long-term health implications related to common, preventable diseases such as obesity, cardiovascular disease, neurodegenerative disease, diabetes, and cancer.

[0004] While pursuing a ketogenic diet and lifestyle and maintaining a state of nutritional ketosis has numerous health benefits, significant barriers remain to pursuing and maintaining a ketogenic state. One such barrier is the difficulty of transitioning into a ketogenic state. The fastest endogenous way to transition into ketosis via depletion of glucose stores in the body is through fasting combined with exercise. This is physically and mentally demanding and can be extremely difficult for even the most motivated and disciplined individuals.

[0005] Numerous studies on exogenous ketone bodies have shown that ingesting compounds that increase blood ketone body levels can provide a variety of clinical benefits, including improved physical and cognitive performance and the treatment of cardiovascular disease, diabetes, neurodegenerative diseases, and epilepsy. Therefore, providing ketone bodies directly to humans and animals as an energy source is desirable. Diets or nutritional supplements may contain carboxylic acids, such as beta-hydroxybutanoic acid (also known as 3-hydroxybutanoic acid or BHB), which is one of the three major ketone bodies (i.e., acetoacetate, acetone, and BHB).

[0006] However, currently known ingestible exogenous ketone bodies have drawbacks that limit their use. Beta-hydroxybutanoic acid, a source of exogenous ketones, has the well-known problem of being highly acidic, limiting the amount and concentration of beta-hydroxybutanoic acid available in ingestible forms. The acidity issue of D-BHB acid has been addressed in some applications by forming β-hydroxybutanoic acid into sodium, magnesium, calcium, and potassium salts. While salts can solve the acidity issue, the use of ketone salts is also limited to very small amounts due to excessive salt content, which can easily cause electrolyte imbalance and have an unpleasant taste except in small amounts. When simply physically mixing BHB acid and salts, the above problems still exist, making it difficult to achieve a uniform mixture.

[0007] Therefore, to solve the problems of the strong acidity and high hygroscopicity of existing BHB acids, as well as the high salt load, gastrointestinal side effects, and unpleasant taste of existing BHB salts, there is a need to find additional substances that can effectively avoid or balance the above problems so that they can be better used as ketogenic substances in dietary or nutritional supplements, and are particularly beneficial for the process preparation and application of solid granules. Summary of the Invention [Means for solving the problem]

[0008] In one aspect, the present invention provides a complex comprising 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate.

[0009] In some embodiments, the complex comprises a 3-hydroxybutyrate anion, a sodium ion, and a hydrogen ion. In some embodiments, the anion in the complex structure comprises a 3-hydroxybutanoate anion, and the cations comprise a sodium ion and a hydrogen ion.

[0010] In some embodiments, the 3-hydroxybutyrate anion content in the complex is greater than the 3-hydroxybutyrate anion content in sodium 3-hydroxybutyrate.

[0011] In some embodiments, the ratio of 3-hydroxybutanoic acid to sodium 3-hydroxybutanoate is 1:10 to 10:1. In some embodiments, the ratio of 3-hydroxybutanoic acid to sodium 3-hydroxybutanoate may be 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, 1:3 to 3:1, 1:2 to 2:1, or 1:1.

[0012] In some embodiments, the complex has 50% or more in the R configuration and 50% or less in the S configuration, or more than 50% in the S configuration and less than 50% in the R configuration.

[0013] In some embodiments, the complex is 3-hydroxybutanoic acid·sodium 3-hydroxybutanoate.

[0014] In some embodiments, the complex has the structure [ka] is.

[0015] In some embodiments, the complex is R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate and / or S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate.

[0016] In some embodiments, the complex contains 50% or more R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate and 50% or less S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate, or greater than 50% S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate and less than 50% R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate. In some embodiments, the complex contains 51-100%, 51-99%, 55-95%, 60-90%, 70-80% R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate; 0-49%, 1-49%, 5-45%, 10-40%, or 20-30% S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate. In some embodiments, the complex contains 51-100%, 51-99%, 55-95%, 60-90%, or 70-80% S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate; or 0-49%, 1-49%, 5-45%, 10-40%, or 20-30% R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate.

[0017] In some embodiments, the complex has the structure [ka] is.

[0018] In some embodiments, the complex is in a crystalline form.

[0019] In some embodiments, the powder X-ray diffraction pattern of the complex comprises peaks at diffraction angles (2θ) of 9.8°±0.2°, 10.8°±0.2°, 18.9°±0.2°, and 31.1°±0.2°.

[0020] In some embodiments, the powder X-ray diffraction pattern of the complex further comprises one or more peaks at diffraction angles (2θ) of 13.4°±0.2°, 21.6°±0.2°, and 32.7°±0.2°.

[0021] In some embodiments, the powder X-ray diffraction pattern of the complex further comprises one or more peaks at diffraction angles (2θ) of 15.1°±0.2°, 23.0°±0.2°, and 31.9°±0.2°.

[0022] In some embodiments, the powder X-ray diffraction pattern of the complex is shown in FIG. 1A, FIG. 1B, or FIG. 1C.

[0023] In some embodiments, the infrared spectrum of the complex is expressed in reciprocal wavelength (cm -1 )(±2cm -1 ), 1715, 1452, 1414, 1368, 1306, 1217, 1148, 1094, 1057, 980, 853, 710, 573, 467 absorption bands.

[0024] In some embodiments, the powder X-ray diffraction pattern of the complex comprises peaks at diffraction angles (2θ) of 6.9°±0.2°, 10.7°±0.2°, 18.1°±0.2°, 22.3°±0.2°, 23.0°±0.2°, 26.8°±0.2°, and 31.2°±0.2°.

[0025] In some embodiments, the powder X-ray diffraction pattern of the complex further comprises one or more peaks at diffraction angles (2θ) of 17.2°±0.2°, 21.6°±0.2°, and 25.8°±0.2°.

[0026] In some embodiments, the powder X-ray diffraction pattern of the complex comprises peaks at diffraction angles (2θ) of 7.7°±0.2°, 10.7°±0.2°, 13.2°±0.2°, 18.7°±0.2°, 21.4°±0.2°, 31.4°±0.2°, and 32.6°±0.2°.

[0027] In some embodiments, the powder X-ray diffraction pattern of the complex further comprises one or more peaks at diffraction angles (2θ) of 15.0°±0.2°, 23.9°±0.2°, and 34.3°±0.2°.

[0028] In some embodiments, the complex is formulated as a food, beverage, supplement, or pharmaceutical.

[0029] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (1) A step of obtaining substance A by one of the following methods: mixing 3-hydroxybutanoic acid with sodium 3-hydroxybutanoate; adding 3-hydroxybutanoic acid to an aqueous solution of an alkaline sodium compound, stirring to remove water, and steaming until nearly dry; or reacting alkyl 3-hydroxybutanoate with water by heating in the presence of a catalyst, cooling, filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and steaming until nearly dry; (2) adding one or more solvents selected from water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in step (1), stirring and cooling, preferably to 0 to 20°C or 0 to 10°C, to precipitate a solid; and (3) filtering and drying the solid, preferably at 35°C to 65°C, to obtain the complex; The present invention provides a 3-hydroxybutanoic acid-sodium 3-hydroxybutanoate complex, which can be obtained by a method including the steps of:

[0030] In some embodiments, the alcohols in step (2) are methanol, ethanol, isopropanol, or n-butanol, with ethanol or isopropanol being preferred; the halogenated hydrocarbons are chlorobenzene, dichlorobenzene, or dichloromethane, with dichloromethane being preferred; the ketones are acetone, methylbutanone, or methylisobutanone, with acetone being preferred; and the esters are ethyl acetate, isopropyl acetate, n-butyl acetate, or isobutyl acetate, with ethyl acetate being preferred.

[0031] In some embodiments, the alkaline sodium compound in step (1) is NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc, or NaOCHO, with NaOH being preferred, and the alkyl 3-hydroxybutanoate is methyl 3-hydroxybutanoate, ethyl 3-hydroxybutanoate, propyl 3-hydroxybutanoate, or butyl 3-hydroxybutanoate, with methyl 3-hydroxybutanoate being preferred.

[0032] In some embodiments, the complex is R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate and / or S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate.

[0033] In some embodiments, the complex is in a crystalline form.

[0034] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (1) A step of obtaining substance A by one of the following methods: mixing 3-hydroxybutanoic acid with sodium 3-hydroxybutanoate; adding 3-hydroxybutanoic acid to an aqueous solution of an alkaline sodium compound, stirring to remove water, and steaming until nearly dry; or reacting alkyl 3-hydroxybutanoate with water by heating in the presence of a catalyst, cooling, filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and steaming until nearly dry; (2) adding one or more solvents selected from water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in step (1), stirring and cooling, preferably to 0 to 20°C or 0 to 10°C, to precipitate a solid; and (3) filtering and drying the solid, preferably at 35°C to 65°C, to obtain the complex; The present invention provides a method for preparing the above complex, comprising:

[0035] In some embodiments, the alcohols in step (2) are methanol, ethanol, isopropanol, or n-butanol, with ethanol or isopropanol being preferred; the halogenated hydrocarbons are chlorobenzene, dichlorobenzene, or dichloromethane, with dichloromethane being preferred; the ketones are acetone, methylbutanone, or methylisobutanone, with acetone being preferred; and the esters are ethyl acetate, isopropyl acetate, n-butyl acetate, or isobutyl acetate, with ethyl acetate being preferred.

[0036] In some embodiments, the alkaline sodium compound in step (1) is NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc, or NaOCHO, with NaOH being preferred, and the alkyl 3-hydroxybutanoate is methyl 3-hydroxybutanoate, ethyl 3-hydroxybutanoate, propyl 3-hydroxybutanoate, or butyl 3-hydroxybutanoate, with methyl 3-hydroxybutanoate being preferred.

[0037] In another aspect, the present invention provides a composition comprising an effective amount of a complex of the present invention and a pharmaceutically acceptable carrier.

[0038] In some embodiments, the composition is applied as a ketogenic agent.

[0039] In some embodiments, the composition is formulated as a food, beverage, supplement, or pharmaceutical.

[0040] In another aspect, the present invention provides the use of the above complex for the preparation of a ketogenic substance for increasing or maintaining blood ketone levels in a subject.

[0041] In some embodiments, the ketogenic substance is a nutritional supplement, an energy therapy, a medical treatment, or a strength and / or endurance sports supplement.

[0042] In another aspect, the present invention provides use of a composition comprising a complex of the present invention and a pharmaceutically acceptable carrier for the preparation of a ketogenic substance for increasing or maintaining blood ketone levels in a subject.

[0043] In some embodiments, the ketogenic substance is a nutritional supplement, an energy therapy, a medical treatment, or a strength and / or endurance sports supplement. [Effects of the Invention]

[0044] Compared with the prior art, the beneficial effects of the complex of the present invention are that it has no unpleasant odor and can effectively avoid problems such as acidity, hygroscopicity, salt load, intestinal side effects, and electrolyte imbalance. Compared with other exogenous ketones, the complex has superior applicability. When administered to a subject, the complex exhibits a comprehensive effect superior to that of the acid or salt alone or a simple physical mixture of the components. On the one hand, the compound of the present invention solves the problems of strong acidity, intestinal side effects, and high hygroscopicity of BHB acids, and also solves the electrolyte imbalance caused by the high salt load of BHB salts. Therefore, as a ketogenic substance, it may have broad application potential in the fields of dietary supplements and foods. [Brief explanation of the drawings]

[0045] [Figure 1A] FIG. 1 is an XRPD diagram of an R-3-hydroxybutanoic acid / R-3-hydroxybutanoate sodium complex of the present invention. [Figure 1B] FIG. 1 is an XRPD diagram of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex of the present invention. [Figure 1C] FIG. 1 is an XRPD diagram of the S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex of the present invention. [Figure 2] FIG. 1 is an infrared spectrum (IR) of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex of the present invention. [Figure 3A] 1 is a Raman spectrum of the R-3-hydroxybutanoic acid / R-3-hydroxybutanoate sodium complex of the present invention. [Figure 3B] 1 shows a Raman spectrum of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex of the present invention. [Figure 3C] 1 is a Raman spectrum of the S-3-hydroxybutanoic acid / S-3-hydroxybutanoate sodium complex of the present invention. [Figure 4A] FIG. 1 is a TGA diagram of an R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex of the present invention. [Figure 4B]FIG. 1 is a TGA diagram of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex of the present invention. [Figure 4C] 1 is a TGA diagram of the S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex of the present invention. [Figure 5A] 1 is a DSC spectrum of the R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex of the present invention. [Figure 5B] 1 is a DSC spectrum of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex of the present invention. [Figure 5C] 1 is a DSC spectrum of the S-3-hydroxybutanoic acid / S-3-hydroxybutanoate sodium complex of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0046] Reference will now be made in detail to preferred embodiments of the invention, examples of which will be further described. While the invention will be described in connection with preferred embodiments, it will be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover alternatives, modifications, and equivalents which may be included within the spirit and scope of the invention as defined by the appended claims. Furthermore, in the detailed description of the invention, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and other features have not been described in detail so as not to unnecessarily obscure aspects of the invention.

[0047] The 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex of the present invention contains 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate in any appropriate ratio, and may be a hydrate having a certain water content, a non-hydrate, or a corresponding crystalline form.

[0048] As used herein, the term "or" is intended to include "and" and "or." In other words, the term "or" can be replaced with "and / or."

[0049] As used herein, the singular forms "a / an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0050] As used herein, the terms "comprise" or "comprises," or variations thereof, are used in an open-ended sense to include items that follow the word, but do not exclude items not specifically mentioned. This also includes the more restrictive verbs "consisting essentially of" and "consisting of."

[0051] As used herein, the terms "about" and "approximately" provide numerical flexibility by providing an endpoint that a given value may be "slightly more than" or "less than." The flexibility of this term can be determined by the particular variables and is within the knowledge of one of ordinary skill in the art to determine based on experience and the relevant explanations herein.

[0052] "β-hydroxybutanoic acid," also known as 3-hydroxybutanoic acid, βHB, or BHB, refers to a compound having the general formula CH3CH2OHCH2COOH. "β-hydroxybutanoic acid derivatives" refer to compounds having the following chemical structure, where X is hydrogen, a metal ion, an amino cation (e.g., an amino acid), or the like. [ka]

[0053] When X is hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is a beta-hydroxybutyrate salt. The compound may be in any desired physical form, such as a crystal, powder, solid, liquid, solution, suspension, or gel.

[0054] As used herein, the term "administration" refers to the process of delivering the disclosed complex or active ingredient to a subject. The complexes of the present invention can be administered in a variety of suitable ways to achieve the desired effect, including orally, intragastrically, and parenterally (referring to intravenous, intraarterial, and other suitable parenteral routes). The complexes of the present invention can be administered to a subject at a therapeutically effective dose and / or frequency to induce or maintain ketosis. In some embodiments, a single dose comprises an amount of about 1-50 grams, or about 2-40 grams, or about 5-30 grams, or about 10-20 grams, or about 0.5-25 grams, or about 0.75-20 grams, or about 1-15 grams, or about 1.5-12 grams. In some embodiments, multiple doses of the complex are administered over a period of time. The administration frequency of the complex can vary based on any of a variety of factors, including the length of time since the previous treatment and the purpose of the treatment. The administration duration of the complex (e.g., the period over which the agent is administered) can vary depending on any of a variety of factors, including the subject's response, the desired therapeutic effect, etc.

[0055] As used herein, the term "effective amount" refers to the amount necessary to achieve the effects taught herein. The amount administered may vary depending on factors such as individual sensitivity, the individual's age, sex, and weight, and the individual's specific response. According to the present disclosure, the size of an appropriate single dose is one that achieves the above-mentioned effects when administered one or more times over an appropriate period of time.

[0056] As used herein, the term "pharmaceutically acceptable" means pharmaceutically, physiologically, dietarily and / or nutritionally acceptable and refers to a composition or agent, material, or combination of compositions and / or dosage forms thereof that, within the scope of sound medical judgment, is suitable for contact with the tissues of human beings and animals, is compatible with the other ingredients of the composition, and is free from excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0057] In some embodiments, the β-hydroxybutanoic acid can be R-β-hydroxybutanoic acid that is endogenously produced by mammals during ketosis, such that administering R-β-hydroxybutanoic acid to a subject provides additional amounts and / or increased plasma levels that can be immediately used by the body, for example, for energy production (e.g., as an alternative energy source to glucose).

[0058] The complexes and / or compositions of the present invention can be used to prepare ketogenic substances for increasing or maintaining blood ketone levels in a subject, including elevating ketone body levels in a subject and inducing and / or maintaining a desired elevated ketone body level (e.g., ketosis) in the subject to which they are administered. "Ketosis" refers to a subject having blood ketone levels within the range of about 0.5 mmol / L to about 16 mmol / L. Ketosis can improve mitochondrial function, reduce reactive oxygen species production, decrease inflammation, and increase neurotrophic factor activity. "Ketoadaptation" refers to prolonging nutritional ketosis (>1 week) to achieve sustained, non-pathological "mild ketosis" or "therapeutic ketosis." In some cases, "elevated ketone body levels" may not mean that the subject is in a state of "clinical ketosis," but nevertheless represents an increased supply of ketones for energy production and / or other beneficial effects of ketone bodies.

[0059] Administration of the complexes and / or compositions of the present invention, as ketogenic agents, can increase or maintain blood ketone levels in a subject and can produce one or more desired effects, including, but not limited to, appetite suppression, weight loss, fat loss, reduced blood glucose levels, improved mental alertness, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased strength, increased muscle mass, or improved body composition.

[0060] In some embodiments, the complex of the present invention can be prepared as a composition together with a vegetatively or pharmaceutically acceptable carrier. In the present invention, the dosage form in which the composition is provided may contain liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient, i.e., suitable for consumption or nutritionally acceptable. Examples of such carriers include non-toxic, compatible substances commonly used in health foods and dietary supplements, as well as pharmaceuticals, such as sugar, starch, cellulose and its derivatives, powdered tragacanth, malt, gelatin, talc, oils, glycols, polyols, esters, agar, alginic acid, pyrogen-free water, isotonic saline, etc.

[0061] In some embodiments, the complexes of the present invention can be administered with other supplements, such as vitamins, minerals, nootropics, and other supplements known in the art. Examples of vitamin, mineral, and herbal supplements that can be added to the ketogenic composition include one or more of vitamin A, vitamin C, vitamin D3, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese, chromium, caffeine, theobromine, theacrine, methylliberin, huperzine A, epicatechin, and enzymes.

[0062] In some embodiments, the complex of the present invention can be provided in solid or powder form. Such solid compositions can be formulated with sufficient ease of handling and manufacturing. The complex may also be provided in liquid form, such as an injection or oral spray, for rapid delivery and absorption. Liquid forms may contain one or more liquid carriers, such as water, ethanol, glycerol, propylene glycol, 1,3-propylene glycol, etc.

[0063] In some embodiments, the complexes of the present invention are available as plugs, strips, pills, pellets, powders, films, capsules, beverages, aerosols, spirits, tinctures, tonics, liquid suspensions, or syrups.

[0064] The complexes and / or compositions of the present invention can be formulated into food and beverage products for human consumption, as well as nutritional supplements, energy therapies, medical treatments, or strength and / or endurance sports supplements, to provide a dietary source of exogenous ketones as ketogenic substances and increase or maintain blood ketone levels in subjects. The resulting products can exhibit a balanced effect of reduced acidity, reduced hygroscopicity, improved taste, improved palatability, uniform appearance, and good ketogenic effects without the problems of intestinal side effects, electrolyte imbalance, and high salt load.

[0065] The following are illustrative of selected embodiments of the present invention and are not intended to limit the scope of the invention.

[0066] Preparation of the complexes of the present invention Example 1: Preparation of R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex 110 grams of R-3-hydroxybutanoic acid, 110 grams of sodium R-3-hydroxybutanoate, and 440 mL of dichloromethane were added to a 1-L reaction bottle, heated to 40°C, stirred to dissolve, and cooled to 0-10°C to precipitate a solid, which was filtered and dried at 40°C to obtain 150 grams of R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate complex.

[0067] Example 2: Preparation of R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 104 grams of R-3-hydroxybutanoic acid, 116 grams of sodium R-3-hydroxybutanoate, and 440 mL of acetone, heated to 60°C, stirred to dissolve, cooled to 0-10°C, and the solid precipitated. The precipitate was filtered and dried at 55°C to obtain 140 grams of R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate complex.

[0068] Example 3: Preparation of R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 200 mL of water and 20 grams of sodium hydroxide, stirred to dissolve, and cooled to below 25°C. 104 grams of R-3-hydroxybutanoic acid was added, stirred for half an hour, and then the water was removed by distillation under reduced pressure. The mixture was steamed until nearly dry, and 200 mL of dichloromethane was added, stirred, and cooled to 0-10°C. The solid precipitated, filtered, and dried at 40°C to obtain 75 grams of R-3-hydroxybutanoic acid·R-3-hydroxybutanoic acid sodium complex.

[0069] Example 4 Preparation of R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 200 mL of water and 20 grams of sodium hydroxide, stirred to dissolve, and cooled to below 25°C. 104 grams of R-3-hydroxybutanoic acid was added, stirred for half an hour, the water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 200 mL of acetone was added, stirred, and cooled to 0-10°C. The solid precipitated, filtered, and dried at 55°C, yielding 98 grams of R-3-hydroxybutanoic acid·R-3-hydroxybutanoic acid sodium complex.

[0070] Example 5: Preparation of R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 60 grams of methyl R-3-hydroxybutanoate, 360 mL of water, and 24 grams of catalyst, and the mixture was heated at 90-95°C for 24 hours until the reaction was complete. The mixture was then cooled to room temperature, the catalyst was filtered off, and the filtrate was added with 50 mL of an aqueous solution of 9 grams of sodium hydroxide. The water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 100 mL of dichloromethane was added, the mixture was stirred, and the mixture was cooled to 0-10°C. The solid was precipitated, filtered, and dried at 40°C to obtain 40 grams of R-3-hydroxybutanoic acid·Sodium R-3-hydroxybutanoate complex.

[0071] Example 6: Preparation of R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 60 grams of methyl R-3-hydroxybutanoate, 360 mL of water, and 24 grams of catalyst, and the mixture was heated at 90-95°C for 24 hours until the reaction was complete. The mixture was then cooled to room temperature, the catalyst was filtered off, and the filtrate was added with 50 mL of an aqueous solution of 9 grams of sodium hydroxide. The water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 100 mL of acetone was added, the mixture was stirred, and the mixture was cooled to 0-10°C. The solid precipitated, filtered, and dried at 55°C to obtain 50 grams of R-3-hydroxybutanoic acid·Sodium R-3-hydroxybutanoate complex.

[0072] Example 7: Preparation of 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 110 grams of 3-hydroxybutanoic acid, 110 grams of sodium 3-hydroxybutanoate, and 440 mL of dichloromethane, heated to 40°C, stirred to dissolve, cooled to 0-10°C, and the solid precipitated. The solid was filtered and dried at 40°C to obtain 155 grams of 3-hydroxybutanoic acid-sodium 3-hydroxybutanoate complex.

[0073] Example 8: Preparation of 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex A 1L reaction bottle was charged with 200mL of water and 20g of sodium hydroxide, stirred to dissolve, cooled to below 25°C, and then 104g of 3-hydroxybutanoic acid was added. After stirring for half an hour, the water was removed by distillation under reduced pressure, and the mixture was steamed until almost dry. 200mL of acetone was added, stirred, cooled to 0-10°C, and the solid precipitated. It was filtered and dried at 60°C, yielding 102g of 3-hydroxybutanoic acid-sodium 3-hydroxybutanoate complex.

[0074] Example 9: Preparation of 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex A 1-liter reaction bottle was charged with 60 grams of methyl 3-hydroxybutanoate, 360 mL of water, and 24 grams of catalyst, and the mixture was heated at 90-100°C for 24 hours until the reaction was complete. The mixture was then cooled to room temperature, the catalyst was filtered off, and the filtrate was added with 50 mL of an aqueous solution of 9 grams of sodium hydroxide. The water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 100 mL of acetone was added, the mixture was stirred, and the mixture was cooled to 0-10°C. The solid precipitated, filtered, and dried at 60°C, yielding 42 grams of 3-hydroxybutanoic acid-sodium 3-hydroxybutanoate complex.

[0075] Example 10: Preparation of S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex A 1-liter reaction bottle was charged with 100 grams of S-3-hydroxybutanoic acid, 100 grams of sodium S-3-hydroxybutanoate, and 440 mL of dichloromethane, heated to 40°C, stirred to dissolve, cooled to 0-10°C, and the solid precipitated. The precipitate was filtered and dried at 40°C to obtain 130 grams of S-3-hydroxybutanoic acid / sodium S-3-hydroxybutanoate complex.

[0076] Example 11: Preparation of S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex A 1-liter reaction bottle was charged with 104 grams of S-3-hydroxybutanoic acid, 116 grams of sodium S-3-hydroxybutanoate, and 440 mL of acetone, heated to 60°C, stirred to dissolve, cooled to 0-10°C, and the solid precipitated. The precipitate was filtered and dried at 55°C to obtain 138 grams of S-3-hydroxybutanoic acid / sodium S-3-hydroxybutanoate complex.

[0077] Example 12: Preparation of S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex A 1-liter reaction bottle was charged with 200 mL of water and 20 grams of sodium hydroxide, stirred to dissolve, and cooled to below 25°C. 104 grams of S-3-hydroxybutanoic acid was added, stirred for half an hour, and the water was removed by vacuum distillation. The mixture was steamed until nearly dry. 200 mL of dichloromethane was added, stirred, and cooled to 0-10°C. The solid precipitated, filtered, and dried at 40°C, yielding 73 grams of S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex.

[0078] Example 13: Preparation of S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex A 1-liter reaction bottle was charged with 200 mL of water and 20 grams of sodium hydroxide, stirred to dissolve, and cooled to below 25°C. 104 grams of S-3-hydroxybutanoic acid was added, stirred for half an hour, the water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 200 mL of acetone was added, stirred, cooled to 0-10°C, and the solid precipitated. It was filtered and dried at 55°C, yielding 98 grams of S-3-hydroxybutanoic acid·S-3-hydroxybutanoic acid sodium complex.

[0079] Example 14: Preparation of S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex A 1-liter reaction bottle was charged with 60 grams of methyl S-3-hydroxybutanoate, 360 mL of water, and 24 grams of catalyst, and the mixture was heated at 90-95°C for 24 hours until the reaction was complete. The mixture was then cooled to room temperature, the catalyst was filtered off, and the filtrate was added with 50 mL of an aqueous solution of 9 grams of sodium hydroxide. The water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 100 mL of dichloromethane was added, the mixture was stirred, and the mixture was cooled to 0-10°C. The solid precipitated, filtered, and dried at 40°C to obtain 42 grams of S-3-hydroxybutanoic acid·S-3-hydroxybutanoic acid sodium complex.

[0080] Example 15: Preparation of S-3-hydroxybutanoic acid / S-3-hydroxybutanoate sodium complex A 1-liter reaction bottle was charged with 60 grams of methyl S-3-hydroxybutanoate, 360 mL of water, and 24 grams of catalyst, and the mixture was heated at 90-95°C for 24 hours until the reaction was complete. The mixture was then cooled to room temperature, the catalyst was filtered off, and the filtrate was added with 50 mL of an aqueous solution of 9 grams of sodium hydroxide. The water was removed by distillation under reduced pressure, and the mixture was steamed until nearly dry. 100 mL of acetone was added, the mixture was stirred, and the mixture was cooled to 0-10°C. The solid precipitated, filtered, and dried at 55°C to obtain 48 grams of S-3-hydroxybutanoic acid·S-3-hydroxybutanoic acid sodium complex.

[0081] Characterization of the complexes of the present invention The complexes prepared in Examples 1 to 15 were subjected to tests such as powder X-ray diffraction (XRPD), elemental analysis, Raman spectroscopy (Raman), infrared spectroscopy (IR), thermogravimetric analysis (TGA), differential thermal analysis (DSC), and dynamic vapor sorption (DVS).

[0082] (Example 16) Powder X-ray Diffraction Powder X-ray diffraction patterns were obtained using a SmartLab 3KW powder X-ray diffractometer under the following conditions: diffraction line: Cu_K-beta (40 KV, 40 mA), scanning rate: 20.00 deg / min, scanning range: 3°-60°. The XRPD pattern of the complex obtained in Example 1 is shown in FIG. 1A, and the XRPD data obtained in Example 1 are shown in Table 1A. The XRPD results of the complexes prepared in Examples 2-6 were essentially consistent with those in Example 1. [Table 1A]

[0083] The XRPD pattern of the complex obtained in Example 7 is shown in FIG. 1B, and the XRPD data obtained in Example 7 are shown in Table 1B. The XRPD results of the complexes prepared in Examples 8 and 9 were basically consistent with those in Example 7. [Table 1B]

[0084] The XRPD pattern of the complex obtained in Example 10 is shown in FIG. 1C, and the XRPD data obtained in Example 10 are shown in Table 1C. The XRPD results of the complexes prepared in Examples 11 to 15 were essentially consistent with those in Example 10. [Table 1C]

[0085] (Example 17) Infrared spectrum The complex of Example 1 was subjected to infrared spectrum analysis using a Shimadzu Fourier transform attenuated total reflection infrared spectrometer. FIG. 2 shows the infrared spectrum (IR) of the complex of Example 1. As can be seen from FIG. 2, the complex has a peak at 1715 cm -1 , 1452cm -1 , 1414cm -1 , 1368cm -1 , 1306cm -1 , 1217cm -1 , 1148cm -1 , 1094cm -1 , 1057cm-1 , 980cm -1 , 853cm -1 , 710cm -1 , 573cm -1 , 467cm -1 The IR results of the complexes prepared in Examples 2 to 15 were basically consistent with those in Example 1.

[0086] (Example 18) Measurement of sodium content and BHB content The sodium content of the complex in Example 1 was measured using ICP-MS according to the second method of GB 5009.268-2016 and the third method of GB 5009.91-2017, and the 3-hydroxybutanoic acid content of the complex was measured using HPLC. The results were consistent with the structure of the complex. The sodium content and 3-hydroxybutanoic acid content of the complexes prepared in Examples 2 to 15 were consistent with those in Example 1.

[0087] (Example 19) NMR ( 1 H / 13 C) Measurement of the complex of Example 1 recorded on an AVIII-HD-400 spectrometer 1 H NMR and 13 The C NMR spectrum is 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 3.92 (H, J = 6.2 Hz, 1H), 2.17 (d, J = 6.5 Hz, 2H), 1.04 (d, J = 6.3 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 176.43, 64.21, 45.62, 23.64. NMR ( 1 H / 13 C) The results were essentially the same as in Example 1.

[0088] (Example 20) Elemental analysis Elemental analysis of the complex of Example 10 revealed that C was 41.7% and H was 6.5%. The elemental analysis results of the other examples were also consistent with those of Example 10, and the results were consistent with the structure of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex.

[0089] (Example 21) Raman Spectrum A characteristic Raman spectrum of the complex can be obtained by Raman spectroscopy. Figure 3A shows the Raman spectrum of the complex of Example 1. The complex of Example 1 has a peak at 2966.80 cm -1 , 2929.23cm -1 , 2912.39cm -1 , 2872.19cm -1 , 2668.47cm -1 , 1619.34cm -1 , 1445.99cm -1 , 1347.96cm -1 , 1213.01cm -1 , 1050.15cm -1 , 962.24cm -1 , 918.94cm -1 , 845.50cm -1 , 65.80cm -1 There is a characteristic absorption peak at -1 The Raman spectrum results of the complexes prepared in Examples 2 to 6 were basically consistent with those of Example 1. FIG. 3B shows the Raman spectrum of the complex of Example 7. The complex of Example 7 exhibited a peak at 435.61 cm -1 , 860.27cm -1 , 929.06cm -1 , 972.40cm -1 , 1058.42cm -1 , 1086.36cm -1 , 1224.66cm -1 , 1360.71cm -1 , 1408.20cm -1 , 1453.85cm -1 , 1629.35cm -1 , 2885.95cm -1 , 2910.89cm -1 , 2942.27cm -1, 2980.01cm -1 There is a characteristic absorption peak at -1 The Raman spectrum results of the complexes prepared in Examples 8 and 9 were basically consistent with those of Example 7. FIG. 3C shows the Raman spectrum of the complex of Example 10. The complex of Example 10 exhibited a peak at 472.68 cm -1 , 858.58cm -1 , 912.63cm -1 , 929.06cm -1 , 972.40cm -1 , 1060.07cm -1 , 1089.64cm -1 , 1151.72cm -1 , 1223.05cm -1 , 1359.12cm -1 , 1456.99cm -1 , 1629.35cm -1 , 2882.01cm -1 , 2925.81cm -1 , 2939.66cm -1 , 2978.71cm -1 There is a characteristic absorption peak at -1 The Raman spectrum results of the complexes prepared in Examples 11 to 15 were basically consistent with those of Example 10.

[0090] (Example 22) Thermogravimetric analysis (TGA) FIG. 4A is a TGA diagram of the complex of Example 1. When the complex was heated from 25°C to 260°C, the weight loss was 46.23%, and when heated from 260°C to 300°C, the weight loss was 11.09%, corresponding to the endothermic peaks at 225.6°C and 276.9°C, respectively. The TGA results of the complexes prepared in Examples 2 to 6 were essentially consistent with those of Example 1. FIG. 4B is a TGA diagram of the complex of Example 7. When the complex was heated from 23.9°C to 50.0°C, the weight loss was 2.02%. The TGA results of the complexes prepared in Examples 8 and 9 were essentially consistent with those of Example 7. FIG. 4C is a TGA diagram of the complex of Example 10. When the complex was heated from 23.8°C to 90.0°C, the weight loss was 0.19%. The TGA results of the complexes prepared in Examples 11 to 15 were essentially consistent with those of Example 10.

[0091] Example 23 Differential Scanning Calorimetry (DSC) FIG. 5A is a DSC spectrum of the complex of Example 1, which has an endothermic peak at 120.01°C ± 3°C. The DSC spectrum of the complexes prepared in Examples 2 to 6 was essentially consistent with that of Example 1. FIG. 5B is a DSC spectrum of the complex of Example 7, which has an endothermic peak at 117.20°C ± 3°C. The DSC spectrum of the complexes prepared in Examples 8 and 9 was essentially consistent with that of Example 7. FIG. 5C is a DSC spectrum of the complex of Example 10, which has an endothermic peak at 120.23°C ± 3°C. The DSC spectrum of the complexes prepared in Examples 11 to 15 was essentially consistent with that of Example 10.

[0092] Measurement of the properties of the complex of the present invention (Example 24) Measurement of water content of the complex of the present invention R-3-hydroxybutanoic acid, sodium R-3-hydroxybutanoate, a mixture of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate, and the R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate complexes from Examples 1 to 6 were tested for moisture content at different times using a KF moisture meter under specific sample storage conditions. The experimental results are shown in Table 2A. [Table 2A]

[0093] 3-hydroxybutanoic acid, sodium 3-hydroxybutanoate, a mixture of 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate, and the 3-hydroxybutanoic acid-sodium 3-hydroxybutanoate complexes from Examples 7 to 9 were tested for moisture content at different times using a KF moisture meter under specific sample storage conditions. The experimental results are shown in Table 2B. [Table 2B]

[0094] S-3-hydroxybutanoic acid, sodium S-3-hydroxybutanoate, a mixture of S-3-hydroxybutanoic acid and sodium S-3-hydroxybutanoate, and the S-3-hydroxybutanoic acid-sodium S-3-hydroxybutanoate complexes from Examples 10 to 12 were tested for moisture content at different times using a KF moisture meter under specific sample storage conditions. The experimental results are shown in Table 2C. [Table 2C]

[0095] The above results indicate that the water content of the R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex is significantly lower than that of R-3-hydroxybutanoic acid, sodium R-3-hydroxybutanoate, and a mixture of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate; the water content of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex is significantly lower than that of 3-hydroxybutanoic acid, sodium 3-hydroxybutanoate, and a mixture of 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate; and the water content of the S-3-hydroxybutanoic acid / sodium S-3-hydroxybutanoate complex is significantly lower than that of S-3-hydroxybutanoic acid, sodium S-3-hydroxybutanoate, and a mixture of S-3-hydroxybutanoic acid and sodium S-3-hydroxybutanoate, thereby increasing the application scenarios of the complex products. The solids of R-3-hydroxybutanoic acid, 3-hydroxybutanoic acid, and S-3-hydroxybutanoic acid are highly hygroscopic and prone to deliquescing, making them unsuitable for use in solid formulations and significantly limiting their application in the fields of solid nutritional products and dietary supplements. The R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex of the present invention has significantly better water absorption performance than R-3-hydroxybutanoic acid, sodium R-3-hydroxybutanoate, and a mixture of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate. The 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex has excellent water absorption properties. The water absorption performance of the S-3-hydroxybutanoic acid / S-3-hydroxybutanoic acid sodium complex is significantly superior to that of S-3-hydroxybutanoic acid, S-3-hydroxybutanoic acid sodium salt, and a mixture of S-3-hydroxybutanoic acid and S-3-hydroxybutanoic acid sodium salt. This complex has a wider range of applications than S-3-hydroxybutanoic acid, S-3-hydroxybutanoic acid sodium salt, and a mixture of S-3-hydroxybutanoic acid and S-3-hydroxybutanoic acid sodium salt. This makes the complex particularly suitable for the preparation and application of solid dosage forms, as mixtures of simple acids and sodium salts can easily become unevenly mixed.

[0096] (Example 25) Stability of the complex of the present invention The stability of R-3-hydroxybutanoic acid, sodium R-3-hydroxybutanoate, a mixture of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate, and the R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate complexes of Examples 1 to 6 was measured at temperatures of 60°C, 70°C, and 80°C, and the experimental results are shown in Table 3A. [Table 3A]

[0097] The stability of 3-hydroxybutanoic acid, sodium 3-hydroxybutanoate, a mixture of 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate, and the 3-hydroxybutanoic acid-sodium 3-hydroxybutanoate complexes of Examples 7 to 9 was measured at temperatures of 60°C, 70°C, and 80°C. The experimental results are shown in Table 3B. [Table 3B]

[0098] The stability of S-3-hydroxybutanoic acid, sodium S-3-hydroxybutanoate, a mixture of S-3-hydroxybutanoic acid and sodium S-3-hydroxybutanoate, and the S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate complexes of Examples 10 to 12 was measured at temperatures of 60°C, 70°C, and 80°C. The experimental results are shown in Table 3C. [Table 3C]

[0099] The above results indicate that the stability of the R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate complex is high and significantly superior to that of R-3-hydroxybutanoic acid and a mixture of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate; the stability of the 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex is high and significantly superior to that of 3-hydroxybutanoic acid and a mixture of 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate; and the stability of the S-3-hydroxybutanoic acid / sodium S-3-hydroxybutanoate complex is high and significantly superior to that of S-3-hydroxybutanoic acid and a mixture of S-3-hydroxybutanoic acid and sodium S-3-hydroxybutanoate.

[0100] The present invention solves the problems of BHB acids (strong acidity, intestinal side effects, high hygroscopicity, and poor stability) and also solves the electrolyte imbalance caused by the high salt load of BHB salts. This complex exhibits a superior overall effect compared to a single acid or salt or a simple physical mixture of the components, has suitable hygroscopicity and stability, and is particularly suitable for the process preparation of solid dosage forms. Furthermore, at appropriate doses, the ketogenic effect of the compounds of the present invention is essentially equivalent to that of BHB acids and BHB salts, and at medium doses, the ketogenic effect is superior to that of BHB salts. Furthermore, the complex prepared by the present invention has high purity, a uniform particle size distribution, good flowability, low adhesion, good bioavailability, and a controllable manufacturing process, low cost, and environmentally friendly.

[0101] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Those skilled in the art can make various changes, modifications, substitutions and alterations to these embodiments without departing from the principles and purpose of the present invention.

Claims

1. A complex comprising 3-hydroxybutanoic acid and sodium 3-hydroxybutanoate.

2. 2. The complex according to claim 1, wherein the anion in the structure of the complex includes a 3-hydroxybutanoic acid anion, and the cation includes a sodium ion and a hydrogen ion.

3. 3. The complex according to claim 1, wherein the ratio of 3-hydroxybutanoic acid to sodium 3-hydroxybutanoate is 1:10 to 10:

1.

4. The complex according to any one of claims 1 to 3, characterized in that the R configuration is 50% or more and the S configuration is 50% or less, or the S configuration is more than 50% and the R configuration is less than 50%.

5. The complex according to any one of claims 1 to 4, characterized in that the complex is 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate.

6. The above complex has the structure 【Chemistry 4】 6. The complex according to claim 1, wherein

7. The complex according to any one of claims 1 to 6, characterized in that the complex is R-3-hydroxybutanoic acid / sodium R-3-hydroxybutanoate and / or S-3-hydroxybutanoic acid / sodium S-3-hydroxybutanoate.

8. The complex according to any one of claims 1 to 6, characterized in that the complex contains 50% or more of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate and 50% or less of S-3-hydroxybutanoic acid and sodium S-3-hydroxybutanoate, or more than 50% of S-3-hydroxybutanoic acid and sodium S-3-hydroxybutanoate and less than 50% of R-3-hydroxybutanoic acid and sodium R-3-hydroxybutanoate.

9. The above complex has the structure 【Chemistry 5】 9. The complex according to claim 7 or 8, wherein

10. 10. The complex according to any one of claims 1 to 9, characterized in that the complex is in crystalline form.

11. 11. The complex according to claim 1, wherein the powder X-ray diffraction pattern of the complex comprises peaks at diffraction angles (2θ) of 9.8°±0.2°, 10.8°±0.2°, 18.9°±0.2°, and 31.1°±0.2°.

12. 12. The complex of claim 11, wherein the powder X-ray diffraction pattern of the complex further includes one or more peaks at diffraction angles (2θ) of 13.4°±0.2°, 21.6°±0.2°, and 32.7°±0.2°.

13. 13. The complex according to claim 11 or 12, wherein the powder X-ray diffraction pattern of the complex further includes one or more peaks at diffraction angles (2θ) of 15.1°±0.2°, 23.0°±0.2°, and 31.9°±0.2°.

14. 11. The complex according to claim 1, wherein the powder X-ray diffraction pattern of the complex is as shown in FIG. 1A, FIG. 1B or FIG. 1C.

15. The infrared spectrum of the above complex is expressed as the reciprocal of the wavelength (cm －１ ) (±2 cm －１ 11. The complex according to claim 1, characterized in that it has absorption bands of 1715, 1452, 1414, 1368, 1306, 1217, 1148, 1094, 1057, 980, 853, 710, 573, 467.

16. 11. The complex according to claim 1, wherein the powder X-ray diffraction pattern of the complex comprises peaks at diffraction angles (2θ) of 6.9°±0.2°, 10.7°±0.2°, 18.1°±0.2°, 22.3°±0.2°, 23.0°±0.2°, 26.8°±0.2°, and 31.2°±0.2°.

17. 17. The complex of claim 16, wherein the powder X-ray diffraction pattern of the complex further includes one or more peaks at diffraction angles (2θ) of 17.2°±0.2°, 21.6°±0.2°, and 25.8°±0.2°.

18. 11. The complex according to claim 1, wherein the powder X-ray diffraction pattern of the complex comprises peaks at diffraction angles (2θ) of 7.7°±0.2°, 10.7°±0.2°, 13.2°±0.2°, 18.7°±0.2°, 21.4°±0.2°, 31.4°±0.2°, and 32.6°±0.2°.

19. 19. The complex of claim 18, wherein the powder X-ray diffraction pattern of the complex further includes one or more peaks at diffraction angles (2θ) of 15.0°±0.2°, 23.9°±0.2°, and 34.3°±0.2°.

20. 20. The complex of any one of claims 1 to 19, wherein the complex is formulated as a food, beverage, supplement or pharmaceutical.

21. (1) a step of obtaining substance A by one of the following methods: mixing 3-hydroxybutanoic acid with sodium 3-hydroxybutanoate; adding 3-hydroxybutanoic acid to an aqueous solution of an alkaline sodium compound, stirring to remove water, and steaming until nearly dry; or reacting alkyl 3-hydroxybutanoate with water by heating in the presence of a catalyst, cooling, filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and steaming until nearly dry; (2) adding one or more solvents selected from water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in the step (1), stirring and cooling the mixture to precipitate a solid; and (3) A step of filtering and drying the solid to obtain the complex. 3-hydroxybutanoic acid / sodium 3-hydroxybutanoate complex, characterized in that it is obtained by a method comprising the steps of:

22. The complex according to claim 21, characterized in that the complex is R-3-hydroxybutanoic acid·sodium R-3-hydroxybutanoate and / or S-3-hydroxybutanoic acid·sodium S-3-hydroxybutanoate.

23. 23. The complex according to claim 21 or 22, characterized in that the complex is in crystalline form.

24. (1) a step of obtaining substance A by one of the following methods: mixing 3-hydroxybutanoic acid with sodium 3-hydroxybutanoate; adding 3-hydroxybutanoic acid to an aqueous solution of an alkaline sodium compound, stirring to remove water, and steaming until nearly dry; or reacting alkyl 3-hydroxybutanoate with water by heating in the presence of a catalyst, cooling, filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and steaming until nearly dry; (2) adding one or more solvents selected from water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in the step (1), stirring and cooling the mixture to precipitate a solid; and (3) A step of filtering and drying the solid to obtain the complex.

11. A process for the preparation of a complex according to any one of claims 1 to 10, characterized in that it comprises

25. 25. The method according to claim 24, wherein the alcohols in step (2) are methanol, ethanol, isopropanol, or n-butanol, the halogenated hydrocarbons are chlorobenzene, dichlorobenzene, or dichloromethane, the ketones are acetone, methylbutanone, or methylisobutanone, and the esters are ethyl acetate, isopropyl acetate, n-butyl acetate, or isobutyl acetate.

26. The alkaline sodium compound in step (1) is NaOH, Na ２ CO ３ , NaHCO ３ , NaOMe, NaOAc or NaOCHO, and the alkyl 3-hydroxybutanoate is methyl 3-hydroxybutanoate, ethyl 3-hydroxybutanoate, propyl 3-hydroxybutanoate or butyl 3-hydroxybutanoate.

27. 24. A composition comprising an effective amount of a complex according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

28. 28. The composition of claim 27, wherein the composition is applied as a ketogenic substance.

29. 29. The composition according to claim 27 or 28, wherein the composition is formulated as a food, drink, supplement or pharmaceutical.

30. 24. Use of a complex according to any one of claims 1 to 23 for the preparation of a ketogenic substance for increasing or maintaining blood ketone levels in a test subject.

31. 31. The use according to claim 30, wherein the ketogenic substance is a nutritional supplement, an energy therapy, a medical treatment or a strength and / or endurance sports supplement.

32. 24. Use of a composition comprising a complex of any one of claims 1 to 23 and a pharmaceutically acceptable carrier for the preparation of a ketogenic substance for increasing or maintaining blood ketone levels in a subject.

33. 33. Use according to claim 32, characterized in that the ketogenic substance is a nutritional supplement, an energy therapy, a medical treatment or a strength and / or endurance sports supplement.

Images