Non-racemic beta-hydroxybutyrate compounds and R-enantiomer-enriched compositions and methods of use

Abstract

The ketogenic composition comprises a non-racemic mixture of beta-hydroxybutyrate salt enriched in the R-enantiomer and an acid. The composition is enriched in the R-enantiomer to increase ketone body activity and improve ketosis achievement, but also contains an amount of the S-enantiomer to provide additional benefits. Beta-hydroxybutyrate is absorbed and utilized more rapidly by the body than salts or esters, enhances flavor, and reduces the need for citric acid or other dietary acids. Beta-hydroxybutyrate salts are absorbed and utilized more slowly by the body and can provide one or more electrolytes. A composition for increasing ketone body levels in a subject can include a nutritionally or pharmaceutically acceptable carrier and a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains about 50.5% to 99.5% enantiomeric equivalents of R-beta-hydroxybutyrate and about 49.5% to 0.5% enantiomeric equivalents of S-beta-hydroxybutyrate.

Description

Technical Field

[0001] This specification discloses mixed, non-racemic beta-hydroxybutyrate compounds, their salts, acids, and esters, and compositions enriched in the R-enantiomer of beta-hydroxybutyrate, and their use in raising the blood levels of ketone bodies in a subject.

Background Art

[0002] During fasting, intense exercise, and / or periods of low carbohydrate consumption, the body's stores of glucose and glycogen can be rapidly depleted. Failure to replenish glucose stores as they are depleted causes the body to metabolically shift to using ketone bodies for energy ( "ketosis"). Ketone bodies can be used by the body's cells as a fuel to meet the body's energy demands, including those of the brain and heart. For example, during prolonged fasting, blood ketone levels can increase to 2-3 mmol / L or more. It has been conventionally understood that when blood ketones rise above 0.5 mmol / L, the heart, brain, and peripheral tissues use ketone bodies (e.g., beta-hydroxybutyrate, and acetoacetate) as a major fuel source. This state is called ketosis. A state where blood levels are between 1.0 mmol / L and 3.0 mmol / L is called "nutritional ketosis".

[0003] When shifting to ketosis, in other words, during ketogenic metabolism in the liver, the body uses dietary fat and body fat as the main energy source. As a result, when shifting to ketosis, it is possible to induce a reduction in body fat by controlling dietary fat intake and maintaining a low carbohydrate intake and blood levels to maintain ketosis.

[0004] During ketosis, the body enters a ketone-producing state and basically burns fat as the main fuel source. In the body, fat is broken down into fatty acids and glycerol. Fatty acids are converted into acetyl-CoA molecules, which are ultimately converted into water-soluble ketone bodies, beta-hydroxybutyrate (i.e., "β-hydroxybutyrate" or "BHB"), acetoacetate (also known as acetylacetonate), and acetone in the liver through ketogenesis. Beta-hydroxybutyrate and acetoacetate are the main ketone bodies used as energy in the body, and acetone is removed and excreted as a byproduct of ketogenesis.

[0005] The metabolism of ketone bodies is associated with several beneficial effects, including anti-seizure effects, promotion of brain metabolism, neuroprotection, muscle preservation properties, and improvement of cognitive and physical abilities. Science-based improvements in the efficiency of cellular metabolism, which are managed by ketone supplementation, have beneficial effects on physical, cognitive, and mental health and may have long-term effects on health regarding common avoidable diseases such as obesity, cardiovascular diseases, neurodegenerative diseases, diabetes, and cancer.

[0006] Pursuing a ketogenic diet and lifestyle and maintaining a state of nutritional ketosis have numerous health benefits, but there are still significant barriers to pursuing and maintaining a ketogenic state. One of those barriers is the difficulty of transitioning to a ketogenic state. The fastest endogenous method of transitioning to ketosis through depletion of glucose stores in the body is through fasting combined with exercise. This is physically and mentally demanding and very difficult even for the most motivated and disciplined individuals.

[0007] Furthermore, the transition to ketosis often involves hypoglycemia, which can frequently cause lethargy and dizziness, and as a result, one may generally fall into an unpleasant physical and mental state commonly known as "low-carb flu". Also, since the body naturally enters an "energy-saving" mode, many people experience downregulation in metabolism. There are also opinions that these transient symptoms can last for a period of two to three weeks. During this transition period, if the subject consumes a meal or snack containing carbohydrates in excess of the limit, ketone production immediately ceases, the body exits the ketosis state, and the body returns to a state where it uses glucose as the main fuel, and the transition to ketosis has to start all over again.

[0008] If the subject succeeds in establishing ketosis, it is necessary to strictly maintain the ratio of carbohydrates and proteins to fat during meals, so maintaining ketosis is similarly difficult, if not so difficult. It is further complicated by the disruption of normal electrolyte balance that often occurs when transitioning to and maintaining a ketogenic state. Due to the depletion and decrease of glycogen storage in the liver and muscles, the body's ability to retain water decreases, the frequency of urination increases, and thereby more electrolytes are lost. Also, the decrease in insulin levels due to ketosis affects the rate at which certain electrolytes are excreted by the kidneys, further reducing the electrolyte levels in the body. The negative effects of electrolyte imbalance include muscle pain, cramps, twitching and weakness, restlessness, anxiety, frequent headaches, extreme thirst, insomnia, fever, heart palpitations or arrhythmias, gastrointestinal symptoms (such as sudden abdominal pain, constipation, or diarrhea), confusion and difficulty concentrating, bone disorders, joint pain, blood pressure changes, appetite or weight changes, fatigue (including chronic fatigue syndrome), joint numbness, and dizziness (especially when standing up suddenly).

[0009] Some of the compositions used to promote ketosis in mammals include a racemic mixture of beta-hydroxybutyrate (RS-beta-hydroxybutyrate or DL-beta-hydroxybutyrate). Other compositions, such as those by Lowery et al. disclosed in US Patent Application Publication No. 2017 / 0296501 (Patent Document 1), include beta-hydroxybutyrate in its endogenous form, i.e., R-beta-hydroxybutyrate, while Lowery et al. do not recommend the use of the non-endogenous enantiomer or S-beta-hydroxybutyrate. Also, other compositions, such as those disclosed in US Patent No. 8,642,654 to Clarke et al. (Patent Document 2), are composed of mostly or all of a single beta-hydroxybutyrate ester, (3R)-hydroxybutyl (3R)-hydroxybutyrate. Other enantiomers, such as (3R)-hydroxybutyl (3S)-hydroxybutyrate, (3S)-hydroxybutyl (3R)-hydroxybutyrate, and (3S)-hydroxybutyl (3S)-hydroxybutyrate, are mostly or all excluded. The exclusion of enantiomers that are not the endogenous form of beta-hydroxybutyrate is based on the view that S-beta-hydroxybutyrate (also known as (3S)-hydroxybutyrate) is ineffective or harmful.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0011] (Summary) Disclosed herein are ketogenic compositions and methods for increasing ketone body levels in a subject, including promoting and / or sustaining ketosis in the subject. Exemplary compositions include a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture is enriched in the R-beta-hydroxybutyrate enantiomer compared to the S-beta-hydroxybutyrate enantiomer, e.g., the R-beta-hydroxybutyrate enantiomer is 50.5% to 99.5% in enantiomeric equivalents and the S-beta-hydroxybutyrate enantiomer is 49.5% to 0.5% in enantiomeric equivalents.

Means for Solving the Problems

[0012] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more (i.e., more than 50% and less than 100%) of the R-beta-hydroxybutyrate enantiomer, which is the endogenous form produced by mammals, than the S-beta-hydroxybutyrate enantiomer (i.e., less than 50% and more than 0%) in order to provide a greater and / or faster ketogenic effect compared to the racemic mixture. Since the R-beta-hydroxybutyrate enantiomer is endogenously produced by mammals during ketosis, administration of the R-beta-hydroxybutyrate enantiomer to a subject results in an additional amount and / or increased plasma levels that can be immediately utilized by the body, such as for producing energy (e.g., as an energy source instead of glucose).

[0013] Nevertheless, contrary to the conventional knowledge of minimizing or eliminating S-beta-hydroxybutyrate, which is not endogenously produced by mammals and is considered unnatural and potentially harmful, the non-racemic mixture contains a significant amount of the S-beta-hydroxybutyrate enantiomer to provide one or more desired effects in mammals, as described herein.

[0014] Furthermore, conventional compositions typically include polymers, oligomers, esters, or salt forms of beta-hydroxybutyrate, while non-racemic mixtures enriched in R-beta-hydroxybutyrate compared to S-beta-hydroxybutyrate may include the free acid forms of R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate. For example, the non-racemic mixture may include one or more salts or esters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, combined with R-beta-hydroxybutyric acid, and optionally S-beta-hydroxybutyric acid. Combining beta-hydroxybutyric acid with one or more beta-hydroxybutyrate salts is beneficial because it reduces electrolyte load, increases absorption rate, improves taste, facilitates formulation, and reduces the need to add citric acid or other edible acids to obtain a composition having a neutral or acidic pH.

[0015] In some embodiments, the compositions disclosed herein may be used in a method of increasing ketone body levels in a subject (including promoting and / or maintaining ketosis in the subject), which includes administering to the subject in need thereof a nutritionally or pharmaceutically effective amount of one or more of the compositions disclosed herein. Examples of beneficial effects of increasing ketone body levels in a subject include one or more of appetite suppression, weight loss, fat loss, reduction of blood glucose levels, improvement of mental acuity, increase in physical energy, improvement of cognitive function, reduction of traumatic brain injury, reduction of the effects of diabetes, improvement of neuropathy, reduction of cancer, reduction of inflammation, prevention of aging, anti-glycation, reduction of epileptic seizures, improvement of mood, enhancement of physical strength, increase in muscle mass, or improvement of body composition.

[0016] In some embodiments, by administering a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomeric ratios or proportions disclosed herein, an increase in the endogenous production of R-beta-hydroxybutyrate and acetoacetate, an endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate, an endogenous conversion of S-beta-hydroxybutyrate to fatty acids and sterols, an extension of ketosis, a metabolism of S-beta-hydroxybutyrate independent of its conversion to R-beta-hydroxybutyrate and / or acetoacetate, an increase in fetal development, an increase in the number of growth years, a decrease in the endogenous production of acetone during ketosis, a signaling by S-beta-hydroxybutyrate that regulates the metabolism of R-beta-hydroxybutyrate and glucose, antioxidant activity, and production of acetyl-CoA are provided, one or more of which is provided.

[0017] The composition may include a nutritionally or pharmaceutically acceptable carrier.

[0018] Additional features and advantages will be described in part in the following description, and in part will be apparent from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing summary and the following detailed description are by way of example and explanation only and are not restrictive of the embodiments or claims described herein.

DETAILED DESCRIPTION

[0019] (Detailed Description) 1. Introduction The compound "beta-hydroxybutyrate" is also known as β-hydroxybutyrate, 3-hydroxybutyrate, βHB, or BHB, and is the deprotonated form of beta-hydroxybutyric acid, a hydroxycarboxylic acid having the general formula CH3CH2OHCH2COOH. The deprotonated form that exists at typical biological pH levels is CH3CH2OHCH2COO - is. The following general chemical structure represents beta-hydroxybutyrate compounds that can be utilized in the disclosed compositions. [Chemical formula] (wherein, X may be hydrogen, a metal ion, an amino cation such as from an amino acid, an alkyl, an alkenyl, an aryl, or an acyl.)

[0020] 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. When X is an alkyl, an alkenyl, an aryl, or an acyl, the compound is a beta-hydroxybutyrate ester. The aforementioned compounds can be in any desired physical form such as a crystal, powder, solid, liquid, solution, suspension, or gel.

[0021] Unless otherwise specified, the term "salt" does not mean or imply any particular physical state such as a crystal, powder, or other solid form that dissolves in water to form a solution or disperses in a liquid to form a suspension or gel. Salts can be formed in solution by at least partially neutralizing beta-hydroxybutyric acid with a strong or weak base such as a hydroxide, carbonate, or bicarbonate of an alkali metal or alkaline earth metal, or a basic amino acid.

[0022] In some cases, the composition can include a mixture of one or more beta-hydroxybutyrate salts and beta-hydroxybutyric acid. Providing R-beta-hydroxybutyrate in its acid form can be beneficial because the absorption response time is much more rapid compared to the salt form. Nevertheless, even though the acid form itself is a liquid with extremely low pH and an unpalatable taste, when made or combined with the salt form and the amount of beta-hydroxybutyric acid is less than in the salt form, the composition can still form the typical solid, powder or other forms of the salt form. In such cases, the form of the combination of the BHB salt and acid has an acceptable pH and taste. BHB compositions containing both the salt and acid forms have advantages such as improved absorption rate, improved bioavailability, reduced electrolyte load, ease of manufacture, significant improvement in taste, and reduction in the need for citric acid or other edible acids to obtain a neutral or acidic pH composition. It will also be understood that beneficial effects can be obtained using a mixture of a BHB salt and / or ester and the acid form of BHB.

[0023] The term "free beta-hydroxybutyric acid" means the sum of non-deprotonated beta-hydroxybutyric acid molecules and deprotonated beta-hydroxybutyric acid molecules. Deprotonated beta-hydroxybutyric acid molecules generally mean molecules that have released a proton to form hydronium ions (H3O+) and beta-hydroxybutyrate anions (e.g., when dissolved in water).

[0024] Free beta-hydroxybutyric acid molecules, when included in a beta-hydroxybutyrate mixed hydrochloride composition in dry powder or other solid form, are typically not significantly deprotonated. In such cases, the fractional amount of free beta-hydroxybutyric acid in the beta-hydroxybutyrate mixed hydrochloride composition on a weight basis is the weight of the free beta-hydroxybutyric acid divided by the total weight of the free beta-hydroxybutyric acid and the beta-hydroxybutyrate salt. On a molar basis, the fractional amount of free beta-hydroxybutyric acid in the beta-hydroxybutyrate mixed hydrochloride composition is the molar equivalent of the free beta-hydroxybutyric acid divided by the sum of the molar equivalents of the free beta-hydroxybutyric acid and the beta-hydroxybutyrate anion provided by the beta-hydroxybutyrate salt.

[0025] When dissolved in water, a portion of the beta-hydroxybutyric acid typically dissociates into beta-hydroxybutyrate anions and hydronium ions (H3O+). As a result, beta-hydroxybutyric acid molecules can exchange protons and cations with the dissolved beta-hydroxybutyrate salt. For the purpose of defining the relative amounts of beta-hydroxybutyric acid and beta-hydroxybutyrate salt in the beta-hydroxybutyrate mixed salt-hydrochloride composition, the dissociation of beta-hydroxybutyric acid molecules and the exchange of protons and cations are not understood to change the molar ratio of free beta-hydroxybutyric acid to beta-hydroxybutyrate anions from the beta-hydroxybutyrate salt. The total amount of free beta-hydroxybutyric acid molecules in solution is the sum of the undeprotonated dissolved beta-hydroxybutyric acid molecules and the beta-hydroxybutyrate anions formed by the deprotonation of beta-hydroxybutyric acid molecules.

[0026] Put another way, the total molar equivalent of beta-hydroxybutyric acid in the solution, whether deprotonated or not, is understood to be the difference between (i) the sum of the molar equivalent of non-deprotonated beta-hydroxybutyric acid molecules and the total molar equivalent of beta-hydroxybutyrate anions in the solution (from all sources), and (ii) the total molar equivalent of cationic charge provided by the cations from the beta-hydroxybutyrate salt compound (which is equal to the total molar equivalent of beta-hydroxybutyrate anions provided by the beta-hydroxybutyrate salt). Alkali metal cations such as sodium and potassium provide 1 molar equivalent of cationic charge per 1 mole of metal cation. On the other hand, alkaline earth metal cations such as magnesium and calcium provide 2 molar equivalents of cationic charge per 1 mole of metal cation. One mole of deprotonated beta-hydroxybutyric acid molecule provides 1 molar equivalent of anionic charge and 1 molar equivalent of cationic charge.

[0027] From the above, the mole fraction of beta-hydroxybutyric acid in the solution with respect to the total number of moles of beta-hydroxybutyrate molecules from the beta-hydroxybutyric acid mixed salt-acid composition in the solution is [(i)-(ii)÷(i)], and the mole fraction of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate salt in the solution is [(ii)÷(i)]. Multiplying each mole fraction by 100 gives the respective percentages in the solution.

[0028] For example, if a 100 molar equivalent beta-hydroxybutyrate mixed salt-acid composition in dry powder form contained 5% free non-deprotonated beta-hydroxybutyric acid and 95% beta-hydroxybutyrate salt on a molar basis, there would be substantially 5 molar equivalents of beta-hydroxybutyric acid molecules and 95 molar equivalents of beta-hydroxybutyrate anions. If there was sufficient water to dissolve the beta-hydroxybutyrate salt and some of the beta-hydroxybutyric acid molecules were deprotonated, the molar equivalent of non-deprotonated beta-hydroxybutyric acid would be less than 5 and the molar equivalent of beta-hydroxybutyrate anions would be greater than 95. The degree of deprotonation of beta-hydroxybutyric acid in solution is related to the pH of the solution.

[0029] Whether beta-hydroxybutyrate is the R-enantiomer or the S-enantiomer depends on the tetrahedral orientation of the hydroxy (or oxy group in the case of an ester) on the 3-carbon (beta-carbon) in relation to the planar carboxyl group.

[0030] Beta-hydroxybutyrate, typically the endogenous form R-beta-hydroxybutyrate, can be utilized by the body of a subject as a fuel source when the glucose level in the subject is low or when the body of the patient receives a supply of beta-hydroxybutyrate in a usable form. Beta-hydroxybutyrate is generally referred to as a "ketone body".

[0031] As used herein, a "ketogenic composition" is formulated to raise ketone body levels in a subject, including inducing and / or sustaining an elevated state of ketone bodies, such as at a desired level of ketosis, in the subject to which it is administered.

[0032] As used herein, "subject" or "patient" refers to a member of the animal kingdom, including, but not limited to, mammals, such as humans and other primates, rodents, fish, reptiles, and birds. The subject may be any animal in need of treatment, therapy, or prevention, or any animal suspected of being in need of treatment, therapy, or prevention. Prevention is meant to be carried out to prevent an event that may occur, such as when high glucose or diabetes is recognized. "Patient" and "subject" are used interchangeably herein.

[0033] The term "unit dose" refers to a dosage form configured to deliver a specific quantity or dose of a composition or its components. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, foods, food additives, beverages (such as flavored, vitamin - fortified, or non - alcoholic), beverage additives (such as flavored, vitamin - fortified, or non - alcoholic), candies, suckers, pastilles, nutraceuticals, food - acceptable sprays (such as flavored mouth sprays), injectables (such as alcohol - free injectables), and suppositories. Such dosage forms can be configured to provide a complete unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a unit dose).

[0034] Another dosage form that can be used to provide a unit dose of a composition or its components is a unit - dose measuring device, such as a cup, scoop, syringe, dropper, spoon, spatula, or colon irrigation device, configured to hold a measured quantity of the composition equal to a complete unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a unit dose). For example, a bulk container, such as a carton, box, can, jar, bag, pouch, bottle, watering can, or flask, containing several unit doses of a composition (e.g., 5 - 250 or 10 - 150 unit doses), can be provided to the user together with a unit - dose measuring device configured to provide a unit dose or a fraction of the composition or its components.

[0035] A kit for providing the compositions disclosed herein in bulk form while providing unit doses of the compositions may include a bulk container that holds an amount of the composition therein and a unit dose measuring device configured to provide a unit dose or a fraction thereof of the composition or its components. One or more unit dose measuring devices may be disposed within the bulk container at the time of sale, may be attached outside the bulk container, may be pre-packaged together with the bulk container within a larger package, or may be provided by a seller or manufacturer for use with one or more bulk containers.

[0036] The kit may include instructions regarding the size of the unit dose or fraction thereof, as well as the method and frequency of administration. The instructions may be provided on the bulk container, may be pre-packaged together with the bulk container, may be placed in the packaging material sold together with the bulk container, or may be provided by a seller or manufacturer (e.g., website, email, flyer, product literature, etc.). The instructions may include a reference to the use of the unit dose measuring device for properly providing the unit dose or fraction thereof. The instructions may additionally or alternatively include a reference to common unit dose measuring devices such as spoons, spatulas, cups, etc. that are not attached to the bulk container (e.g., in case the provided unit dose measuring device is lost or forgotten). In such cases, the kit may be constructed by the end user according to the instructions provided on the bulk container or provided by the seller regarding the method of properly providing the unit dose or fraction of the product, composition.

[0037] As used herein, "ketosis" refers to a subject having blood ketone levels in the range of about 0.5 mmol / L to about 16 mmol / L in a subject. Ketosis can improve mitochondrial function, reduce the production of reactive oxygen species, reduce inflammation, and increase the activity of neurotrophic factors. As used herein, "ketone adaptation" refers to long-term nutritional ketosis (>1 week) to obtain a maintained non-pathological "mild ketosis" or "therapeutic ketosis".

[0038] In some cases, "elevated ketone body levels" may not mean that the subject is in a state of "clinical ketosis", but nevertheless means an increase in the supply of ketones for generating energy and / or exerting other beneficial effects of ketone bodies. For example, a "ketone adapted" subject may not necessarily have elevated serum levels of ketone bodies, but can utilize available ketone bodies more rapidly compared to a subject who is not "ketone adapted". In such cases, "elevated ketone body levels" may refer to the total amount and / or ratio of ketone bodies utilized by the subject, rather than plasma levels.

[0039] The term "short-chain triglyceride" (SCT) refers to a molecule having a glycerol backbone with three medium-chain fatty acids attached. Medium-chain fatty acids can range in length from 2 to 5 carbon atoms. Examples of medium-chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and the like. An example of an SCT is tributyrin.

[0040] The term "medium-chain triglyceride (MCT)" refers to a molecule having a glycerol backbone with three medium-chain fatty acids attached. Medium-chain fatty acids can range in length from 6 to 12 carbon atoms, and are likely to range in length from 8 to 10 carbon atoms. Examples of fatty acids are caprylic acid, which has 8 carbon molecules and is also known as octanoic acid, and capric acid, which has 10 carbon molecules and is also known as decanoic acid. MCTs, medium-chain fatty acids, and mono- and diglycerides are ketone body precursors that can provide an additional source for the production of ketone bodies independently of beta-hydroxybutyrate.

[0041] The term "long-chain triglyceride" (LCT) refers to a molecule having a glycerol backbone with three medium-chain fatty acids attached. Long-chain fatty acids can have more than 12 carbon atoms in length.

[0042] As used herein, the term "administer" or "administering" is used to describe the process of delivering the disclosed compositions to a subject. The compositions can be administered in a variety of ways including orally, intragastrically, and parenterally (referring to intravenous and intraarterial, as well as other suitable parenteral routes).

[0043] II. Non-racemic beta-hydroxybutyrate compositions A composition for increasing ketone body levels in a subject, including promoting and / or maintaining ketosis, comprises a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate enriched in the R-enantiomer (i.e., greater than 50% and less than 100% R-beta-hydroxybutyrate in enantiomeric equivalents, and less than 50% and greater than 0% S-beta-hydroxybutyrate in enantiomeric equivalents).

[0044] In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprises from 50.5% to 99.5%, 51% to 99%, 52% to 98%, 53% to 97%, 55% to 95%, 55% to 89%, 57% to 87%, or 60% to 80% R-beta-hydroxybutyrate enantiomer in enantiomeric excess, and from 49.5% to 0.5%, 49% to 1%, 48% to 2%, 47% to 3%, 45% to 5%, 45% to 11%, 43% to 13%, 41% to 15%, or 40% to 20% S-beta-hydroxybutyrate enantiomer in enantiomeric excess.

[0045] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrate enantiomer, which is the endogenous form produced by mammals, than the S-beta-hydroxybutyrate enantiomer in order to provide a greater and / or faster ketogenic effect compared to the racemic mixture. Since the R-beta-hydroxybutyrate enantiomer is endogenously produced by mammals during ketosis, administration of the R-beta-hydroxybutyrate enantiomer provides an additional amount that is immediately available in the body, such as for energy production (e.g., as an energy source instead of glucose), and / or increases plasma levels, compared to the racemic mixture of R,S-beta-hydroxybutyrate (also known as DL-beta-hydroxybutyrate). The presence of the S-enantiomer allows this effect to be modulated and extended.

[0046] Contrary to conventional wisdom that minimizes or eliminates S-beta-hydroxybutyrate, which is non-natural and potentially harmful and not endogenously produced by mammals, the non-racemic mixture contains a significant amount of the S-beta-hydroxybutyrate enantiomer to provide one or more desired effects in a mammal. For example, administering S-beta-hydroxybutyrate together with R-beta-hydroxybutyrate results in (1) increased endogenous production of R-beta-hydroxybutyrate and acetoacetate, (2) endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate, (3) endogenous conversion of S-beta-hydroxybutyrate to fatty acids and sterols, (4) extension of ketosis, (5) metabolism of S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and / or acetoacetate, (6) increased fetal development, (7) increased growth years, (8) decreased endogenous production of acetone during ketosis, (9) signaling by S-beta-hydroxybutyrate to regulate the metabolism of R-beta-hydroxybutyrate and glucose, (10) antioxidant activity, and (11) production of acetyl-CoA, and one or more of these results may be provided.

[0047] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be used to produce one or more desired effects in a subject, including, but not limited to, appetite suppression, weight loss, fat loss, reduction of blood glucose levels, improvement of mental acuity, increase in physical energy, improvement of cognitive function, reduction of traumatic brain injury, reduction of the effects of diabetes, improvement of neuropathy, reduction of cancer, reduction of inflammation, prevention of aging, anti-glycation, reduction of epileptic seizures, improvement of mood, enhancement of physical strength, increase in muscle mass, or improvement of body composition.

[0048] The composition may contain a nutritionally or pharmaceutically acceptable carrier.

[0049] R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be provided in various forms such as salts and / or esters, along with an amount of the free acid form. The percent enantiomer equivalent for each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is defined as the molar amount of either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate divided by the total molar amount of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. The amount of any cation forming a salt and / or alcohol forming an ester is excluded and not included in the calculation to determine the ratio of percent enantiomer equivalent for each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. For example, weights such as cations, alcohols, complexing agents, etc. can be considered so as not to affect the enantiomer equivalent of R-BHB and S-BHB.

[0050] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate should not contain more than 88%, or 87%, or 86%, or 85% of the enantiomer equivalent of (3R)-hydroxybutyl (3R)-hydroxybutyrate monoester in order not to overload the composition with R-beta-hydroxybutyrate and a large amount of precursors that are readily convertible to R-beta-hydroxybutyrate, namely R-1,3-butanediol and the monoester of R-beta-hydroxybutyrate (i.e., (3R)-hydroxybutyl (3R)-hydroxybutyrate monoester).

[0051] In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is provided in a composition containing a dietetically or pharmaceutically acceptable carrier. Examples include powders, liquids, tablets, capsules, foods, food additives, beverages, beverage additives, candies, candy bars, lozenges, nutritional supplements, sprays, injections, and suppositories.

[0052] In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be provided as a salt, such as one or more salts of an alkali metal, alkaline earth metal, transition metal, amino acid, or metabolite of an amino acid. Examples include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, zinc salts, iron salts (as iron(II) and / or iron(III)), chromium salts, manganese salts, cobalt salts, copper salts, molybdenum salts, selenium salts, arginine salts, lysine salts, leucine salts, isoleucine salts, histidine salts, ornithine salts, citrulline salts, glutamine salts, and creatine salts.

[0053] The non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate can be provided as one or more esters such as mono-, di-, tri-, oligo-, and polyesters. For example, the monoester of ethanol, the monoester of 1-propanol, the monoester of 1,2-propanediol, the diester of 1,2-propanediol, the monoester of 1,3-propanediol, the diester of 1,3-propanediol, the monoester of S-, R-, or S-R-1,3-butanediol, the diester of S-, R-, or S-R-1,3-butanediol, the monoester of glycerin, the monoester of (3S)-hydroxybutyl(3S)-hydroxybutyrate, the monoester of (3R)-hydroxybutyl(3S)-hydroxybutyrate, the diester of glycerin, the triester of glycerin, the ester of acetoacetate, the dimer, trimer, oligomer, and polyester having repeating units of beta-hydroxybutyrate, and the complex oligomer or polymer of beta-hydroxybutyrate with one or more other hydroxycarboxylic acids such as lactic acid, citric acid, acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, and malic acid, and / or beta-hydroxybutyrate with one or more diols such as 1,3-propanediol and 1,3-butanediol, and one or more polyacids such as tartaric acid, citric acid, malic acid, succinic acid, and fumaric acid. It can contain the (3R)-hydroxybutyl(3R)-hydroxybutyrate monoester, but should not exceed 88%, or 87%, or 86%, or 85% in enantiomeric equivalent of the composition.

[0054] The non-racemic mixture may comprise one or more salt forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with a relatively small amount of the acid form of R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate. The ratio of the salt form to the acid form of R-beta-hydroxybutyrate is not necessarily the same as the ratio of the salt form to the acid form of S-beta-hydroxybutyrate. This allows for more flexible and broader advantages in controlling the pharmacokinetics and electrolyte balance of the composition.

[0055] In some embodiments, the non-racemic mixture comprises less than 100% of one or more beta-hydroxybutyrate salts and more than 0% free beta-hydroxybutyric acid, e.g., in molar equivalents, up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97% of one or more R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate salts, and in molar equivalents, at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%, and less than 25%, 20%, 15%, 10%, 8%, 6%, 5%, 4%, or 3% free R-beta-hydroxybutyric acid and / or free S-beta-hydroxybutyric acid.

[0056] If the non-racemic mixture contains a large amount of the R-enantiomer as compared to the S-enantiomer, it is possible to obtain a composition having a neutral or other desired pH even when using a higher ratio of free S-beta-hydroxybutyric acid as compared to the S-beta-hydroxybutyrate salt. That is, even if the relative amount of S-beta-hydroxybutyric acid is higher as compared to the S-beta-hydroxybutyrate salt, if the amount of the R-beta-hydroxybutyrate salt is large, the total amount of acid may be relatively small.

[0057] In other embodiments, the non-racemic mixture may include one or more ester forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, in combination with a relatively small amount of the acid form of R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate. In still other embodiments, the non-racemic mixture may include both the salt form and the ester form of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, in combination with a relatively small amount of the acid form of R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate.

[0058] In some embodiments, the composition may include at least one medium-chain fatty acid, or a mono-, di-, or triglyceride of at least one medium-chain fatty acid, wherein the medium-chain fatty acid has 6 to 12 carbon atoms, preferably 8 to 10 carbon atoms. The composition may include at least one short-chain fatty acid, or a mono-, di-, or triglyceride of the at least one short-chain fatty acid, wherein the short-chain fatty acid has less than 6 carbon atoms. Although less preferred, the composition may include at least one long-chain fatty acid having more than 12 carbon atoms or a mono-, di-, or triglyceride of the long-chain fatty acid.

[0059] Examples of short-chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid. Examples of medium-chain fatty acids include caproic acid, caprylic acid, capric acid, and lauric acid. Examples of long-chain fatty acids include myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids.

[0060] Examples and sources of medium-chain fatty acids, or their esters such as medium-chain triglycerides, include coconut oil, coconut milk powder, palm oil, palm kernel oil, caprylic acid, capric acid, isolated medium-chain fatty acids (such as isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid, etc.), any medium-chain triglyceride in purified or natural form (such as coconut oil), and ester derivatives of medium-chain fatty acid ethoxylated triglycerides, enontriglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives, and triglyceride derivatives, as well as salts of medium-chain triglycerides. Ester derivatives optionally include alkyl ester derivatives such as methyl, ethyl, propyl, butyl, hexyl, etc.

[0061] Administration of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate results in elevated and sustained blood levels of ketone bodies, thereby allowing utilization of the metabolic and physiological advantages of sustained ketosis. By raising the blood levels of ketone bodies, a subject is enabled to more flexibly select a diet compared to methods aimed at inducing and maintaining ketosis based solely on diet (e.g., fasting and / or restricting carbohydrate intake). For example, a subject administered an appropriate amount of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate will be able to occasionally consume carbohydrate- or sugar-based foods without risking a ketogenic state and without reverting to a glucose-based metabolic state. Further, such administration facilitates the transition to a ketogenic state and reduces or eliminates typical adverse effects associated with the transition to a ketogenic state.

[0062] In some embodiments, the ketogenic composition further contains a therapeutically effective amount of vitamin D3. Vitamin D3 is thought to act with magnesium and calcium to promote good bone health and prevent unwanted calcification of soft tissues. In preferred embodiments, the vitamin D3 is contained in an amount such that the average daily dose of the ketogenic composition contains, for example, from about 200 IU ("International Units") to about 8000 IU of vitamin D3, or from about 400 IU to about 4000 IU, or from about 600 IU to about 3000 IU. In some embodiments, the vitamin D3 is contained in an amount such that the average daily dose of the ketogenic composition contains, for example, from about 5 μg to about 200 μg of vitamin D3, or from about 10 μg to about 100 μg, or from about 15 μg to about 75 μg.

[0063] Some embodiments also include one or more additional ketone precursors or supplements. These additional ketone precursors or supplements may include acetoacetate, ketone esters, and / or other compounds that raise blood ketone levels without adding more electrolytes into the bloodstream. Other additives may include metabolites that enhance the effect or promote the transport of ketone bodies to the mitochondria, nootropics such as caffeine, theobromine, and L-alpha glycerophosphocholine (“alpha GPC”).

[0064] The composition may include flavorings that help mask the bad taste of beta-hydroxybutyrate compounds. These include essential oils such as peppermint, natural and artificial sweeteners, and other flavorings known in the art.

[0065] In some embodiments, the ketogenic composition may further contain one or more additional components configured to reduce the hygroscopicity of the composition. For example, various anti-caking agents, flow agents, and / or desiccants may be included in a safe type and amount for ingestion. Such additional components may include one or more of aluminosilicates, ferrocyanides, carbonates or bicarbonates, silicates (e.g., sodium silicate or calcium silicate), silica, phosphates (e.g., dicalcium phosphate or tricalcium phosphate), talc, powdered cellulose, calcium carbonate, etc.

[0066] III. Administration In some embodiments, the compositions disclosed herein may be used in a method of increasing ketone body levels in a subject, including promoting and / or maintaining ketosis, the method including administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of one or more of the compositions disclosed herein. Examples of beneficial effects of increasing ketone body levels in a subject, including promoting and / or maintaining ketosis, include appetite suppression, weight loss, fat loss, reduction of blood glucose levels, improvement of mental acuity, increase of physical energy, improvement of cognitive function, reduction of traumatic brain injury, reduction of the effects of diabetes, improvement of neuropathy, reduction of cancer, reduction of inflammation, anti-aging, anti-glycation, reduction of epileptic seizures, improvement of mood, enhancement of physical strength, increase of muscle mass, or improvement of body composition.

[0067] By administering a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomeric ratios or proportions described herein, an increase in the endogenous production of R-beta-hydroxybutyrate and acetoacetate, an endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate, an endogenous conversion of S-beta-hydroxybutyrate to fatty acids and sterols, an extension of ketosis, a metabolism of S-beta-hydroxybutyrate independent of its conversion to R-beta-hydroxybutyrate and / or acetoacetate, an increase in fetal development, an increase in the number of growth years, a decrease in the endogenous production of acetone during ketosis, a signaling by S-beta-hydroxybutyrate that regulates the metabolism of R-beta-hydroxybutyrate and glucose, antioxidant activity, and the production of acetyl CoA, among others, are provided.

[0068] The ketogenic compositions described herein can be administered to a subject in a therapeutically effective amount and / or at a frequency that induces or maintains ketosis. In some embodiments, a single dose comprises an amount of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate ranging from about 0.5 grams to about 25 grams, or from about 0.75 grams to about 20 grams, or from about 1 gram to about 15 grams, or from about 1.5 grams to about 12 grams.

[0069] In some embodiments, the ketogenic composition can include or be administered with other supplements known in the art, such as vitamin D3, vitamins, minerals, nootropics, etc. Examples of vitamins, minerals, and herbal supplements that can be added to the ketogenic composition include one or more of vitamin A, vitamin C, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese, chromium, caffeine, theobromine, theacrine, methylsynephrine, huperzine A, epicatechin, and enzymes.

[0070] In some embodiments, the composition may further comprise one or more short-chain fatty acids, medium-chain fatty acids, long-chain fatty acids, fatty acid esters, or mono-, di-, or triglycerides of short-chain, medium-chain, or long-chain fatty acids to provide an additional source of ketone bodies as described herein and to maintain ketosis for a longer period compared to the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate itself. In some embodiments, the composition is preferably administered such that the ratio of the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to the short-chain, medium-chain, or long-chain fatty acid (or its ester) ranges from about 4:1 to about 1:4, or from about 2:1 to about 1:2, or from about 1.5:1 to about 1:1.5.

[0071] In some embodiments, the subject preferably follows a ketogenic diet that restricts the intake of carbohydrates and proteins during the administration period of the composition. For example, the subject may restrict dietary intake to a ratio of about 65% fat, about 25% protein, and about 10% carbohydrates. The resulting therapeutic ketosis provides a rapid and sustained keto adaptation as a metabolic therapy for a wide range of metabolic disorders, and provides nutritional support for therapeutic fasting, weight loss, and performance improvement. Based on this, the composition is typically administered once, twice, or three times a day to subjects who desire to promote and / or maintain a ketogenic state.

[0072] In a preferred embodiment, the ketogenic composition may be orally administered in a powder form such as a solid and / or powder mixture (e.g., powder-filled gelatin capsules), a strongly pressed tablet, or other oral administration routes known in the art.

[0073] In some embodiments, the composition is administered in multiple doses over a period of time. The dosing frequency of the composition may vary depending on various factors such as the timing of treatment from pretreatment, the purpose of treatment, etc. The administration period of the composition (e.g., the period during which the drug is administered) may vary depending on various factors including the response of the subject, the desired effect of the treatment, etc.

[0074] The amount of the composition administered may vary depending on factors such as the degree of individual sensitivity, the age, gender, and weight of the individual, and the idiosyncratic reactions of the individual. A "therapeutically effective amount" is the amount necessary to promote a therapeutically effective result (i.e., therapeutic ketosis) in vivo. According to the present disclosure, an appropriate single-dose size is an amount that can prevent or alleviate (reduce or eliminate) symptoms in a patient when administered one or more times over an appropriate period.

[0075] The amount of the composition to be administered is determined by the efficacy, absorption, distribution, metabolism, and excretion rate of the unused ketone bodies, electrolytes, the method of administration, the specific disorder being treated, and other factors known to those skilled in the art. Taking into account the severity of the condition to be alleviated, the dosage should be sufficient to affect a desired response, such as a therapeutic or prophylactic response to a specific disorder or condition. The composition may be administered in a single dose or divided and administered over time. It should be understood that the administration can be adjusted according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

Example

[0076] IV. Example Described below are exemplary non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate compositions useful for increasing ketone levels in a subject, and other ketogenic compositions, including inducing and / or maintaining a ketogenic state in the subject to which they are administered. It should be recognized that the beta-hydroxybutyrate compounds described in the examples may be in the form of salts, esters, dimers, trimers, oligomers, and polymers as described herein. Of importance from the perspective of the examples is the enantiomeric ratio or proportion of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate.

[0077] In some cases, the composition may be a mixture of beta-hydroxybutyrate salts, a mixture of beta-hydroxybutyrate esters, a mixture of beta-hydroxybutyrate salts and esters, a mixture of beta-hydroxybutyrate salts and free beta-hydroxybutyric acid, a mixture of beta-hydroxybutyrate esters and free beta-hydroxybutyric acid, or a mixture of beta-hydroxybutyrate salts, beta-hydroxybutyrate esters, and free beta-hydroxybutyric acid to provide a desired electrolyte balance, taste, and / or pharmacokinetic response. Further, the composition may be admixed with short-chain, medium-chain, or long-chain fatty acids, esters, glycerides, and other supplements disclosed herein to provide a desired level of elevated ketone bodies and other effects.

[0078] Example 1 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 51% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 49% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture. On the other hand, the presence of the S-beta-hydroxybutyrate enantiomer results in a longer-lasting ketosis state and / or other benefits disclosed herein.

[0079] The non-racemic mixture can be readily administered as a ketogenic composition in, for example, powder form as a nutritional supplement mixed with food or drink, in the form of one or more capsules or tablets, or in liquid form such as a mouse spray.

[0080] Example 2 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 52% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 48% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, at a given dosage, the onset of ketosis is accelerated compared to the same dosage of the racemic mixture. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided.

[0081] Example 3 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 53% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 47% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, at a given dosage, the onset of ketosis is accelerated compared to the same dosage of the racemic mixture. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided.

[0082] Example 4 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 55% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 45% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and / or other benefits disclosed herein are provided.

[0083] Example 5 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 57% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 43% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1-4. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and / or other benefits disclosed herein are provided compared to a composition containing 90-100% R-beta-hydroxybutyrate enantiomer in enantiomeric conversion.

[0084] Example 6 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 59% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 41% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, at a given dosage, the onset of ketosis is accelerated compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 5. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided compared to compositions containing 90 to 100% of the R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents.

[0085] Example 7 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 65% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 35% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, at a given dosage, the onset of ketosis is accelerated compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 6. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided compared to compositions containing 90 to 100% of the R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents.

[0086] Example 8 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 70% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 30% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, at a given dosage, the onset of ketosis is accelerated compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 7. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided compared to compositions containing 90-100% of the R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents.

[0087] Example 9 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 75% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 25% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, at a given dosage, the onset of ketosis is accelerated compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 8. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided compared to compositions containing 90-100% of the R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents.

[0088] Example 10 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 80% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 20% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 9. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided compared to a composition containing 90-100% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents.

[0089] Example 11 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 85% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 15% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 10. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-lasting ketosis state and / or other benefits disclosed herein are provided compared to a composition containing 90-100% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents.

[0090] Example 12 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing 89% R-beta-hydroxybutyrate enantiomer in enantiomeric equivalents and 11% S-beta-hydroxybutyrate enantiomer in enantiomeric equivalents. Since the non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 11. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer ketosis state and / or other benefits disclosed herein are provided compared to a composition containing 90 to 100% of the R-beta-hydroxybutyrate enantiomer in enantiomeric terms.

[0091] Example 13 By mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of an R-beta-hydroxybutyrate and an S-beta-hydroxybutyrate composition, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared, providing R-beta-hydroxybutyrate enantiomers in enantiomeric equivalents of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 99.5%, and S-beta-hydroxybutyrate enantiomers in enantiomeric equivalents of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%. Provided that the non-racemic mixture does not contain (3R)-hydroxybutyl (3R)-hydroxybutyrate monoester (i.e., the monoester of R-1,3-butanediol and R-beta-hydroxybutyrate) in enantiomeric equivalents of more than 88%, or 87%, or 86%, or 85%. Since the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomers, the onset of ketosis is accelerated at a given dosage compared to the same dosage of the racemic mixture or the non-racemic mixtures of Examples 1 to 12.

[0092] Example 14 Any of the foregoing examples is modified by combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with a food or pharmaceutically acceptable carrier.

[0093] Example 15 Any of the foregoing examples is modified by combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more medium-chain triglycerides and / or one or more medium-chain fatty acids and / or one or more mono- or diglycerides of medium-chain fatty acids.

[0094] Example 16 By combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more short-chain triglycerides and / or one or more short-chain fatty acids and / or one or more mono- or diglycerides of short-chain fatty acids, any of the foregoing examples is modified.

[0095] Example 17 By combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more long-chain triglycerides and / or one or more long-chain fatty acids and / or one or more mono- or diglycerides of long-chain fatty acids, any of the foregoing examples is modified.

[0096] Example 18 By combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more dietary supplements such as vitamin D3, vitamins, minerals and other dietary supplements known in the art, any of the foregoing examples is modified.

[0097] Example 19 Any of the foregoing examples is modified by including one or more salts of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid, providing a mixture of R- and S-beta-hydroxybutyrate salts and free R- and / or S-beta-hydroxybutyric acid. Here, the mixture contains less than 100% of one or more beta-hydroxybutyrate salts and more than 0% free beta-hydroxybutyric acid, up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97% by molar equivalent of one or more R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate salts, and at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3% by molar equivalent of free R-beta-hydroxybutyric acid and / or free S-beta-hydroxybutyric acid.

[0098] Example 20 Any of the foregoing examples is modified by including one or more esters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid, providing a mixture of the ester form of R- and S-beta-hydroxybutyrate and free R- and / or S-beta-hydroxybutyric acid. Here, the non-racemic mixture contains less than 100% of one or more beta-hydroxybutyrate esters and more than 0% free beta-hydroxybutyric acid.

[0099] The present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. Accordingly, the scope of the present invention is indicated rather by the appended claims than by the foregoing description. All modifications which fall within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

**Claim 1** A composition for administering a ketone body to a subject, comprising: a non-racemic mixture of R-β-hydroxybutyrate and S-β-hydroxybutyrate, comprising from 50.5% to 99.5% of R-β-hydroxybutyrate and from 49.5% to 0.5% of S-β-hydroxybutyrate in enantiomeric equivalents, wherein the non-racemic mixture of R-β-hydroxybutyrate and S-β-hydroxybutyrate comprises: at least one R-β-hydroxybutyrate salt, at least one S-β-hydroxybutyrate salt, and at least one of R- or S-β-hydroxybutyric acid, and wherein the non-racemic mixture comprises at least one of calcium R-β-hydroxybutyrate, calcium S-β-hydroxybutyrate, magnesium R-β-hydroxybutyrate, or magnesium S-β-hydroxybutyrate, wherein the composition is in powder form, and wherein the non-racemic mixture comprises a combination of from 90 to 99.9% of R-β-hydroxybutyrate salt and S-β-hydroxybutyrate salt in molar equivalents, and from 10% to 0.1% of R-β-hydroxybutyric acid and / or S-β-hydroxybutyric acid in molar equivalents. **Claim 2** The composition according to claim 1, wherein the non-racemic mixture comprises from 51% to 99% of R-β-hydroxybutyrate and from 49% to 1% of S-β-hydroxybutyrate in enantiomeric equivalents. **Claim 3** The composition according to claim 1 or 2, wherein the non-racemic mixture comprises from 52% to 98% of R-β-hydroxybutyrate and from 48% to 2% of S-β-hydroxybutyrate in enantiomeric equivalents. **Claim 4** The composition according to any one of claims 1 to 3, wherein the non-racemic mixture comprises from 53% to 97% of R-β-hydroxybutyrate and from 47% to 3% of S-β-hydroxybutyrate in enantiomeric equivalents. **Claim 5** The composition according to any one of claims 1 to 4, wherein the non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt in a molar equivalent of 94% to 99.5%, and R-beta-hydroxybutyric acid and / or S-beta-hydroxybutyric acid in a molar equivalent of 6% to 0.5%.

6. The composition according to any one of claims 1 to 5, wherein the non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt in a molar equivalent of 96% to 99%, and R-beta-hydroxybutyric acid and / or S-beta-hydroxybutyric acid in a molar equivalent of 4% to 1%.

7. The composition according to any one of claims 1 to 6, wherein the non-racemic mixture further comprises at least one additional lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, or amino acid salt of R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate.

8. The composition according to any one of claims 1 to 7, further comprising at least one short-chain fatty acid having less than 6 carbons, or a mono-, di-, or triglyceride of the at least one short-chain fatty acid.

9. The composition according to any one of claims 1 to 8, further comprising at least one supplement selected from vitamins, minerals, nootropics, and herbal supplements.

10. A composition for administering ketone bodies to a subject, a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, comprising more than 50% and less than 100% of R-beta-hydroxybutyrate in enantiomeric equivalents and less than 50% and more than 0% of S-beta-hydroxybutyrate in enantiomeric equivalents, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprises at least one R-beta-hydroxybutyrate salt or ester, at least one S-beta-hydroxybutyrate salt or ester, and a non-racemic mixture comprising at least one of R- or S-beta-hydroxybutyric acid. The composition is provided as, or contained within, tablets, capsules, powders, foods, food additives, flavored beverages, vitamin-enriched beverages, non-alcoholic beverages, flavored beverage additives, vitamin-enriched beverage additives, non-alcoholic beverage additives, candies, stick candies, lozenges, nutritional supplements, flavored mouth sprays, or suppositories, such that the composition provides a unit dose of 0.5 g to 25 g of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture comprises a combination of 90 to 99.9 mol% of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt, and 10% to 0.1 mol% of R-beta-hydroxybutyric acid and / or S-beta-hydroxybutyric acid, a composition.

11. The composition according to claim 10, wherein the non-racemic mixture comprises 50.5% to 99.5% of R-beta-hydroxybutyrate in enantiomeric equivalents, and 49.5% to 0.5% of S-beta-hydroxybutyrate in enantiomeric equivalents.

12. The composition according to claim 10 or 11, wherein the non-racemic mixture comprises a combination of 94% to 99.5 mol% of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt, and 6% to 0.5 mol% of R-beta-hydroxybutyric acid and / or S-beta-hydroxybutyric acid.

13. The composition according to any one of claims 10 to 12, wherein the non-racemic mixture comprises at least one lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, or amino acid salt of R-beta-hydroxybutyrate and / or S-beta-hydroxybutyrate, and the composition is a powder.

14. The composition according to any one of claims 10 to 13, further comprising at least one supplement selected from vitamins, minerals, nootropics, and herbal supplements.

15. A composition for administering a ketone body to a subject, A food or pharmaceutically acceptable carrier selected from the group consisting of tablets, capsules, powders, foods, food additives, flavored beverages, vitamin fortified beverages, non-alcoholic beverages, flavored beverage additives, vitamin fortified beverage additives, non-alcoholic beverage additives, candies, stick candies, lozenges, nutritional supplements, flavored mouth sprays, and suppositories, and, An enantiomerically enriched mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, comprising more than 50% and less than 100% R-beta-hydroxybutyrate in enantiomeric equivalents and less than 50% and more than 0% S-beta-hydroxybutyrate in enantiomeric equivalents, wherein said enantiomerically enriched mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is At least one R-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate ester, At least one S-beta-hydroxybutyrate salt or S-beta-hydroxybutyrate ester, and, An enantiomerically enriched mixture comprising at least one of R- or S-beta-hydroxybutyric acid, Wherein said enantiomerically enriched mixture comprises a molar equivalent combination of 90 to 99.9% of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt, and 10% to 0.1% of R-beta-hydroxybutyric acid and / or S-beta-hydroxybutyric acid in molar equivalents, A composition, wherein said food or pharmaceutically acceptable carrier provides a unit dose of from 0.5 g to 25 g of the enantiomerically enriched mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate.

16. A kit for administering a ketone body to a subject, comprising The composition according to any one of claims 1 to 15, A container in which said composition is placed, and, A measuring device configured to hold a unit dose or a fraction thereof of said composition, wherein the unit dose of said composition comprises from about 0.5 g to about 25 g of said enantiomerically enriched mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate,

17. The kit according to claim 16, wherein said container is selected from the group consisting of cartons, boxes, cans, jars, bags, pouches, bottles, pitchers, and flasks.

18. The kit according to claim 16 or 17, wherein the measuring device is selected from the group consisting of a cup, a scoop, a syringe, a spatula, and a spoon.

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