CN113747890A

CN113747890A - Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use

Info

Publication number: CN113747890A
Application number: CN202080027568.6A
Authority: CN
Inventors: 盖瑞·米列特
Original assignee: Axsex Global Science Co ltd
Current assignee: Axsex Global Science Co ltd; Access Global Sciences LLC
Priority date: 2019-02-11
Filing date: 2020-02-10
Publication date: 2021-12-03
Also published as: JP7448555B2; JP2024014874A; EP3923925A1; WO2020167690A1; AU2020221569A1; CA3129541A1; EP3923925A4; JP2022520205A

Abstract

The ketogenic composition includes a racemic mixture of R-and S-beta-hydroxybutyrate and a racemic mixture of R-and S-beta-hydroxybutyrate. The compositions contain the R-enantiomer to elevate ketone bodies and increase the rate at which ketosis is achieved, and also contain an equivalent amount of the S-enantiomer to provide replacement benefits. R-and S- β -hydroxybutanoic acid are absorbed and utilized by the body more quickly than salts or esters, enhance taste, and reduce the need to include citric acid or other edible acids. R-and S-beta-hydroxybutyrate are more slowly absorbed and utilized by the body and may provide one or more electrolytes. The ketogenic composition may comprise a dietetically or pharmaceutically acceptable carrier and a racemic mixture of R-and S-beta-hydroxybutyrate and acid. The composition contains less than 100 mole equivalents of total R, S-beta-hydroxybutyrate and greater than 0 mole equivalents of R, S-beta-hydroxybutyrate.

Description

Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use

Technical Field

Disclosed herein are racemic β -hydroxybutyrate compounds, particularly salts and acids of racemic β -hydroxybutyrate, and the use of racemic β -hydroxybutyrate mixed salt-acid compositions for producing elevated blood ketone body levels in a subject.

Background

During periods of fasting, extreme exercise, and/or low carbohydrate consumption, the in vivo glucose and glycogen stores are rapidly utilized and may be rapidly depleted. When the glucose stores are depleted, failure to replenish glucose can lead to the body's metabolic shift to the production and use of ketone bodies to harvest energy ("ketosis"). Ketone bodies can be used as fuel by cells of the body to meet the energy needs of the body, including the brain and heart. During a long fasting period, for example, blood ketone levels can increase to 2-3mmol/L or more. It is generally understood that when blood ketones rise above 0.5mmol/L, heart, brain and peripheral tissues use ketone bodies (e.g., beta-hydroxybutyrate and acetoacetate) as the primary fuel source. This condition is called ketosis. Blood concentrations were between 1.0mmol/L and 3.0mmol/L, a condition known as "ketosis".

In the transition to ketosis, or in other words during ketogenic metabolism of the liver, the body uses dietary and body fat as the main energy source. Thus, once ketosis occurs, one can maintain ketosis by controlling dietary fat intake and maintaining low carbohydrate intake and blood levels, resulting in loss of body fat.

When in ketosis, the body is in a ketogenic state and burns mainly fat as its main fuel. The body breaks down fat into fatty acids and glycerol and converts the fatty acids into acetyl-coa molecules which are then ultimately converted by ketogenesis into the water-soluble ketone bodies beta-hydroxybutyrate (i.e., "beta-hydroxybutyrate" or "BHB"), acetoacetate (also known as acetylacetone) and acetone in the liver. Beta-hydroxybutyrate and acetoacetate are the major ketone bodies used by the body for energy, while acetone is removed and excreted as a by-product of ketogenesis.

The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, protective muscle properties, and improved cognitive and physical performance. Based on scientific increases in cellular metabolic efficiency, management by ketone supplementation has beneficial effects on physical, cognitive and mental health, and long-term effects on health for common avoidable diseases (such as obesity, cardiovascular diseases, neurodegenerative diseases, diabetes and cancer).

Despite the many health advantages of seeking ketogenic diets or lifestyles and maintaining a ketogenic state, there are significant obstacles to seeking and maintaining a ketogenic state. One of these obstacles is the difficulty in transitioning to the ketogenic state. The fastest intrinsic route to ketosis is to deplete the body's glucose stores through fasting coupled with exercise. This is physically and emotionally demanding and even challenging for the most motivated and autonomous people.

Furthermore, the transition to ketosis is often accompanied by hypoglycemia, which in many people can lead to somnolence and dizziness, resulting in uncomfortable physiological and psychological states, commonly referred to as "low carbohydrate flu". In addition, many people experience a down regulation of metabolism when the body naturally enters an "energy saving" mode. Some believe that these transient symptoms may last for two to three weeks. During this transition period, if the subject consumes more than a limited amount of carbohydrates in the diet or snack, ketogenesis is immediately terminated, leaving the body out of the ketotic state. The body then switches back to glucose as the primary fuel and the transition to ketosis must begin anew.

Maintaining ketosis behavior is also difficult, if not more difficult, if the subject successfully establishes ketosis, because of the need to maintain a strict dietary ratio of carbohydrates and proteins to fat. The disruption of normal electrolyte balance can complicate matters further when transitioning to and maintaining the ketogenic state. The reduced glycogen stores and decrease in liver and muscle decrease the body's ability to retain water, resulting in more frequent urination and, correspondingly, greater electrolyte loss. In addition, the decrease in insulin levels caused by ketosis affects the rate at which the kidneys extract certain electrolytes, which also reduces electrolyte levels in the body. Negative effects of electrolyte imbalance include muscle pain, spasticity, convulsions and weakness, restlessness, anxiety, frequent headaches, feeling very thirsty, insomnia, fever, palpitations or arrhythmia, digestive problems (such as spasticity, constipation or diarrhea), mental and attention deficit, bone disorders, joint pain, changes in blood pressure, changes in appetite or weight, fatigue (including chronic fatigue syndrome), joint numbness, and dizziness (especially when standing suddenly).

Some compositions for promoting ketosis in mammals include those disclosed in U.S. patent publication No. 2017/0296501 to Lowery et al, which contains an endogenous form of beta-hydroxybutyrate or R-beta-hydroxybutyrate, while Lowery et al discourages the use of non-endogenous enantiomers or S-beta-hydroxybutyrate and racemic mixtures of R-and S-beta-hydroxybutyrate. Others, such as those disclosed in U.S. patent No. 8,642,654 to Clarke et al, consist mostly or entirely of a single beta-hydroxybutyrate (3R) -hydroxybutyl (3R) -hydroxybutyrate. Omission of the enantiomer that is not the endogenous form of beta-hydroxybutyrate is based on the notion that S-beta-hydroxybutyrate (also known as (3S) -hydroxybutyrate) is ineffective or even detrimental.

Disclosure of Invention

Disclosed herein are racemic R, S- β -hydroxybutyrate mixed salt-acid compositions and methods for increasing the level of ketone bodies in a subject, comprising promoting and/or maintaining ketosis in a subject for an extended period of time.

The racemic R, S-beta-hydroxybutyrate mixed salt-acid compositions disclosed herein comprise a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate ("R, S-beta-hydroxybutyrate") and a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate ("R, S-beta-hydroxybutyrate"). A "racemic mixture" of R, S- β -hydroxybutyrate includes enantiomeric equivalent (50:50) of R-and S- β -hydroxybutyrate. A "racemic mixture" of R, S-hydroxybutyric acid includes enantiomeric equivalent amounts (50:50) of R-and S- β -hydroxybutyric acid.

R-beta-hydroxybutyrate is an endogenous form produced by mammals and S-beta-hydroxybutyrate is delivered into the body by exogenous supplementation through the administration of a racemic RS-beta-hydroxybutyrate mixed salt-acid composition. Thus, the racemic RS- β -hydroxybutyrate mixed hydrochloride-acid composition comprises separate components that function differently in vivo but together provide enhanced ketogenic effects, including higher sustained blood ketone levels than administration of the R- β -hydroxybutyrate compound alone. The R, S-beta-hydroxybutyrate mixed salt-acid composition provides at least one "double racemic stack" of beta-hydroxybutyrate compounds.

The R- β -hydroxybutyrate enantiomer is endogenously produced by the mammal during ketosis, thus exogenously administered R- β -hydroxybutyrate mixed salt-acid component provides additional amounts and/or increased plasma levels of R- β -hydroxybutyrate that can be immediately utilized by the body, for example, for energy production (e.g., as an alternative energy source for glucose). The S- β -hydroxybutyrate component which is not endogenously produced by the mammal supplements the R- β -hydroxybutyrate component and produces the desired effect in the mammal produced by the one or more non-R- β -hydroxybutyrate components.

For example, administration of the S- β -hydroxybutyrate mixed salt-acid component with the R- β -hydroxybutyrate mixed salt-acid component in an enantiomeric equivalent ratio may result in at least one of the following: (1) increasing endogenous production of R-beta-hydroxybutyrate and acetoacetate; (2) endogenously converting the S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenously converting the S-beta-hydroxybutyrate component to fatty acids and sterols; (4) prolongation of ketosis; (5) the metabolism of the S- β -hydroxybutyrate component is independent of conversion to R- β -hydroxybutyrate and/or acetoacetate; (6) increased fetal development; (7) the growth years are increased; (8) decreased endogenous production of acetone during ketosis; (9) signaling by modulating the R-beta-hydroxybutyrate and the S-beta-hydroxybutyrate components of glucose metabolism; (10) antioxidant activity; and (11) production of acetyl-coenzyme a.

Exogenous delivery of racemic R, S- β -hydroxybutyrate mixed salt-acid compositions can advantageously provide relatively rapid increases in blood ketone body levels, primarily through the R- β -hydroxybutyrate mixed salt-acid component, particularly R- β -hydroxybutyrate, and in addition relatively more consistently increase blood ketone body levels primarily through the S- β -hydroxybutyrate mixed salt-acid component. This racemic R, S- β -hydroxybutyrate mixed hydrochloride-acid composition is therefore able to effectively and relatively rapidly assist subjects in inducing ketosis while providing sustained and prolonged delivery of ketone bodies to the blood stream through the modulating effect of the S- β -hydroxybutyrate mixed hydrochloride-acid component in providing the body' S desired ketogenic benefit.

Combining R, S- β -hydroxybutyrate with one or more R, S- β -hydroxybutyrate is highly beneficial as it reduces electrolyte loading, increases absorption, improves taste, facilitates easier formulation and reduces the need to add citric acid or other edible acid to obtain a composition with a neutral or acidic pH.

In some embodiments, the racemic R, S- β -hydroxybutyrate mixed salt-acid compositions described herein can be combined (e.g., directly mixed or co-administered) with one or more other dietetically and/or pharmaceutically acceptable supplements/drugs to form a combined supplement. The unique properties of the racemic R, S-beta-hydroxybutyrate mixed salt-acid composition can beneficially enhance the combination supplement compared to other similar combination supplements using a beta-hydroxybutyrate composition consisting of or enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate. For example, a composition intended to increase lipolysis and/or lipoxidation (referred to herein as a "fat burning agent" component) may be combined with a racemic R, S- β -hydroxybutyrate mixed salt-acid composition to form a combined supplement with a synergistic lipolysis and/or fat burning effect. In another example, a composition intended to increase enhanced mental alertness, cognition and/or mood (referred to herein as the "nootropic" component) can be combined with a racemic R, S- β -hydroxybutyrate mixed salt-acid composition to form a combined supplement with synergistic cognitive, alertness and/or mood effects.

In some embodiments, the racemic R, S- β -hydroxybutyrate mixed hydrochloride-acid compositions disclosed herein are useful in methods of increasing ketone body levels in a subject (including promoting and/or maintaining ketosis in a subject) comprising 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 increased ketone body levels in a subject include one or more of appetite suppression, weight loss, fat loss, decreased blood glucose levels, improved mental alertness, anxiolytic effect (anxiolytic), faster response time, increased physical performance, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.

The composition may include a nutritionally or pharmaceutically acceptable carrier.

Embodiments include a "racemic stack" of at least four different beta-hydroxybutyrate compounds. The R-beta-hydroxybutyrate and S-beta-hydroxybutyrate are provided in the form of their free acids (i.e. R-beta-hydroxybutyrate and S-beta-hydroxybutyrate), salts (i.e. R-beta-hydroxybutyrate and S-beta-hydroxybutyrate) and optionally their esters (i.e. R-beta-hydroxybutyrate and S-beta-hydroxybutyrate). Providing beta-hydroxybutyrate as a double racemic stack that incorporates at least four different forms of beta-hydroxybutyrate (or as a triple racemic stack that incorporates six different forms) can advantageously allow for the use of higher amounts of beta-hydroxybutyrate for a given dose administered and/or allow for the use of more doses per day. Each form of beta-hydroxybutyrate generally has its specific positive characteristics and negative side effects. Stacking different forms of beta-hydroxybutyrate may provide more positive properties than using it alone. Similarly, stacking different forms of beta-hydroxybutyrate reduces or mitigates the negative side effects of each particular form of beta-hydroxybutyrate, which can be "dispersed" and limited. In either case, the stack increases or maximizes the total dose of beta-hydroxybutyrate that can be effectively delivered.

Additional features and advantages will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments disclosed or claimed herein.

Drawings

FIG. 1A illustrates that when a "stacked" dose of at least two different forms of racemic R, S- β -hydroxybutyrate is used, higher amounts of β -hydroxybutyrate are administered as compared to the single form of racemic R, S- β -hydroxybutyrate;

FIG. 1B illustrates expected relative ratios of undesirable side effects resulting from treatment with various formulations of beta-hydroxybutyrate, wherein a "double-stacked" (i.e., double racemic stack) formulation comprising 1) free R, S-beta-hydroxybutyrate and (2) R, S-beta-hydroxybutyrate and a "triple-stacked" (i.e., triple racemic stack) formulation further comprising R, S-beta-hydroxybutyrate on top of the double stack is expected to allow for administration of a greater amount of beta-hydroxybutyrate and/or a reduction in the incidence or intensity of side effects as compared to administration of a single form of beta-hydroxybutyrate;

FIG. 2 compares the expected release profiles of the R, S-beta-hydroxybutyrate stack composition with the free acid, salt and ester single forms and the R-beta-hydroxybutyrate stack, indicating that the stacked R, S-composition provides an extended overall release profile with a larger area under the profile (AUC); and

figure 3 illustrates the expected relative rates of lipolysis and/or lipoxidation resulting from treatment with a combination weight supplement including a beta-hydroxybutyrate component and another weight loss supplement and shows a higher total amount of lipolysis and/or lipoxidation (area under the curve) for the combination supplement using a racemic R, S-beta-hydroxybutyrate component compared to a similar combination supplement/drug using a beta-hydroxybutyrate component enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

Detailed Description

I. Definition of

The compound "beta-hydroxybutyrate", also known as beta-hydroxybutyrate, 3-hydroxybutyrate, beta HB or BHB, is the deprotonated form of beta-hydroxybutyrate, which is of the general formula CH₃CH₂OHCH₂Hydroxy carboxylic acid of COOH. At typical biological pH levels, the deprotonated form is CH₃CH₂OHCH₂COO^-. The general chemical structure shown below represents a beta-hydroxybutyrate compound useful in the disclosed compositions:

wherein the content of the first and second substances,

x may be hydrogen, a metal ion, an amino cation (e.g. from an amino acid), an alkyl, alkenyl, aryl or acyl group.

When X is hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is beta-hydroxybutyrate. When X is alkyl, alkenyl, aryl or acyl, the compound is beta-hydroxybutyrate. The aforementioned compounds may be in any desired physical form, such as crystals, powders, solids, liquids, solutions, suspensions or gels.

The term "racemic R, S-beta-hydroxybutyrate" means that an equal enantiomeric amount (50:50) of total R-and S-beta-hydroxybutyrate is present in the composition. The terms "racemic R, S-beta-hydroxybutyrate" and "racemic R, S-beta-hydroxybutyrate" refer to the presence of an equal enantiomeric amount (50:50) of total R-and S-beta-hydroxybutyrate in the composition. The term "racemic R, S- β -hydroxybutyrate" means that an enantiomeric equivalent (50:50) of R-and S- β -hydroxybutyrate is present in the composition. The terms "racemic R, S- β -hydroxybutyrate" and "racemic R, S- β -hydroxybutyrate" refer to the presence of an enantiomeric equivalent (50:50) of total R-and S- β -hydroxybutyrate in the composition.

The term "mixed salt of R, S-beta-hydroxybutyrate-acid composition" means that there is an enantiomeric equivalent of one or more R-beta-hydroxybutyrate and one or more S-beta-hydroxybutyrate in the composition and an enantiomeric equivalent (50:50) of free R-beta-hydroxybutyrate and free S-beta-hydroxybutyrate in the composition.

The term "R, S- β -hydroxybutyrate" does not denote or imply any particular physical state, e.g. crystalline, powder, other solid form, dissolved in water to form a liquid solution, dispersed in a liquid to form a suspension or gel. Salts may be formed in solution, for example, by at least partially neutralizing beta-hydroxybutyrate with strong or weak bases, such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, basic amino acids, and the like.

The term "free β -hydroxybutyrate" refers to the sum of the unprotonated and deprotonated β -hydroxybutyrate molecules. Deprotonated β -hydroxybutyrate molecules are generally referred to as liberating a proton to form the hydronium ion (H)₃O +) and the beta-hydroxybutanoate anion (e.g., dissolved in water).

When included in the beta-hydroxybutyrate mixed salt-acid composition as a dry powder or other solid form, the free beta-hydroxybutyrate molecules are generally not deprotonated to any significant extent. In this case, the weight fraction of free beta-hydroxybutyrate in the beta-hydroxybutyrate mixed salt-acid composition is the weight of free beta-hydroxybutyrate divided by the total weight of free beta-hydroxybutyrate and beta-hydroxybutyrate. The fraction of free beta-hydroxybutyrate in the beta-hydroxybutyrate mixed salt-acid composition on a molar basis is the molar equivalent of free beta-hydroxybutyrate divided by the sum of the molar equivalents of free beta-hydroxybutyrate and the beta-hydroxybutyrate anion provided by the beta-hydroxybutyrate.

When dissolved in water, a portion of the beta-hydroxybutyrate is typically split into beta-hydroxybutyrate anions and hydronium (H)₃O +. As a result, the beta-hydroxybutyrate molecule can exchange protons and cations with dissolved beta-hydroxybutyrate. To define the relative amounts of beta 0-hydroxybutyrate and beta 1-hydroxybutyrate in the beta 2-hydroxybutyrate mixed salt-acid composition, dissociation of the beta-hydroxybutyrate molecule and exchange of protons and cations should not be understood to alter the molar ratio of free beta-hydroxybutyrate relative to the beta-hydroxybutyrate anion from the beta-hydroxybutyrate. The total amount of free β -hydroxybutyrate molecules in solution is the sum of the non-deprotonated dissolved β -hydroxybutyrate molecules and the β -hydroxybutyrate anions formed by deprotonation of the β -hydroxybutyrate molecules.

In other words, the total molar equivalent of β -hydroxybutyrate in solution, whether deprotonated or not, should be understood as the difference between (i) and (ii) below: (i) the sum of the molar equivalents of the non-deprotonated β -hydroxybutyrate molecules and the total molar equivalents of β -hydroxybutyrate anions in solution (from all sources) and (ii) the total molar equivalents of cationic charge provided by the cation of the β -hydroxybutyrate compound (which is equivalent to the total molar equivalents of β -hydroxybutyrate anions provided by the β -hydroxybutyrate). Alkali metal cations (such as sodium and potassium) that provide 1 mole of cationic charge per mole of metal cation. Alkaline earth metal cations (e.g., magnesium and calcium), on the other hand, provide 2 moles of cationic charge per mole of metal cation. 1 mole of deprotonated β -hydroxybutyrate molecules provides 1 mole of anionic charge and 1 mole of cationic charge.

In view of the above, the mole fraction of beta-hydroxybutyrate in solution relative to the total number of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate mixed salt-acid composition in solution is [ (i) - (ii)/i ], and the mole fraction of beta-hydroxybutyrate molecules from beta-hydroxybutyrate in solution is [ (ii)/i ]. The mole fraction of each substance was multiplied by 100 to give the percentage of each substance in solution.

For example, if the beta-hydroxybutyrate mixed salt-acid composition in a dry powder state contains 5% free non-deprotonated beta-hydroxybutyrate and 95% beta-hydroxybutyrate (on a molar basis), there are essentially 5 molar equivalents of beta-hydroxybutyrate molecules and 95 molar equivalents of beta-hydroxybutyrate anions. When there is sufficient water to dissolve the beta-hydroxybutyrate, and if a portion of the beta-hydroxybutyrate molecules are deprotonated, the molar equivalent of the non-deprotonated beta-hydroxybutyrate will be less than 5 and the molar equivalent of the beta-hydroxybutyrate anion will be greater than 95. The degree of deprotonation of beta-hydroxybutyrate in solution is pH dependent.

The beta-hydroxybutyrate is a tetrahedral orientation with the R-or S-enantiomer dependent on the relationship of the hydroxyl group on the 3-carbon (beta-carbon) to the planar carboxyl group.

Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate produced by a mammal, in an endogenous form, can be used by the body of a patient as a fuel source in situations where the glucose level in the subject is low or when the patient is supplemented with a usable form of beta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as "ketone bodies".

As used herein, a "ketogenic composition" is formulated to increase ketone body levels in a subject, including inducing and/or maintaining a state of elevated ketone bodies (e.g., ketosis) at a desired level in a subject to which it is administered.

As used herein, "subject" or "patient" refers to a member of the kingdom animalia, including mammals, such as, but not limited to, humans and other primates; rodents, fish, reptiles, and birds. The subject may be any animal in need of treatment, or prevention, or suspected of being in need of treatment, or prevention. Prevention refers to taking measures to prevent a possible occurrence, for example in the case of a determination of hyperglycemia or diabetes. "patient" and "subject" are used interchangeably herein.

As used herein, "ketosis" refers to a subject having blood ketone levels (including the enantiomer of beta-hydroxybutyrate, acetoacetate, and acetone) in the range of about 0.5mmol/L and about 16mmol/L in the 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, "ketoadaptation" refers to long-term nutritional ketosis (>1 week) to achieve persistent nonpathological "mild ketosis" or "therapeutic ketosis".

In some cases, "elevated ketone body levels" may not mean that the subject is in a "clinical ketosis" state, but still has an elevated ketone supply for energy production and/or to achieve other beneficial effects of ketone body metabolism and signaling. For example, a "ketone-adapted" subject does not necessarily have elevated ketone body serum levels, but is able to utilize available ketone bodies more quickly than a subject that is not "ketone-adapted". In this context, "elevated ketone body levels" can refer to the total amount and/or ratio of ketone bodies utilized by the subject, rather than the plasma levels themselves.

The term "administration" or "administering" is used herein 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 (meaning intravenous and intraarterial, and other suitable parenteral routes), and the like.

The term "combination supplement" is used herein to describe the combination of a beta-hydroxybutyrate component with one or more other supplements and/or drugs. The beta-hydroxybutyrate component and one or more other supplements and/or drugs may be combined directly, for example by mixing together in the same tablet, capsule, mixed powder or other dosage form, or for example by placing the individual components in the same package, even if not directly mixed. However, in other embodiments, it is not necessary to directly combine the individual components prior to administration in order to fall within the scope of the present disclosure. For example, the individual components may be administered to a subject individually, but sufficiently close in time (e.g., within about 8,6, 4, 2, 1, or 0.5 hours of each other) to be considered co-administered and thus part of a "combination supplement".

Racemic R, S-beta-hydroxybutyrate mixed salt-acid compositions

A composition for increasing ketone body levels in a subject, including promoting and/or maintaining ketosis, comprises a racemic R, S-beta-hydroxybutyrate mixed salt-acid composition comprising (1) 50% enantiomeric equivalents of one or more R-beta-hydroxybutyrate and 50% enantiomeric equivalents of one or more S-beta-hydroxybutyrate and (2) 50% enantiomeric equivalents of R-beta-hydroxybutyrate and 50% enantiomeric equivalents of S-beta-hydroxybutyrate. The composition may optionally comprise 50% enantiomeric equivalents of one or more R-beta-hydroxybutyrate and 50% enantiomeric equivalents of one or more S-beta-hydroxybutyrate. The racemic mixture of the mixed salt-acid component of R, S- β -hydroxybutyrate may provide a synergistic effect, for example when used in combination with other components. In this case, the combined salt and acid forms of R, S- β -hydroxybutyrate have an acceptable pH and taste. The R, S-beta-hydroxybutyrate mixed salt-acid compositions have significant advantages over racemic R, S-beta-hydroxybutyrate and esters, including increased absorption, increased bioavailability, lower electrolyte loading, ease of manufacture, significantly improved taste, and reduced need for citric acid or other edible acids to obtain compositions with neutral or acidic pH.

In some embodiments, the racemic R, S- β -hydroxybutyrate mixed salt-acid composition comprises less than 100% racemic R, S- β -hydroxybutyrate and greater than 0% free racemic R, S- β -hydroxybutyrate. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition can comprise 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% on a molar basis, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96% or 97% of total racemic R, S-beta-hydroxybutyrate, 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%, and less than 25%, 20%, 15%, 10%, 8%, 6%, 5%, 4% or 3% of total free racemic R, S- β -hydroxybutyrate. The foregoing percentages are expressed on a molar basis (e.g., moles of free R, S- β -hydroxybutyrate relative to the total moles of R, S- β -hydroxybutyrate compound in salt and acid forms).

The racemic mixture of the R- β -hydroxybutyrate mixed salt-acid component and the S- β -hydroxybutyrate mixed salt-acid component comprises equal amounts of the R- β -hydroxybutyrate enantiomer (an endogenous form produced by the mammal) and the S- β -hydroxybutyrate enantiomer (not naturally produced or found by the mammal) in order to provide enhanced ketogenic effects not possible with the enantiomers delivered alone or in enriched form.

For example, the R- β -hydroxybutyrate enantiomer is endogenously produced by the mammal during ketosis, thus administration of the R- β -hydroxybutyrate mixed hydrochloride-acid component to a subject provides additional amounts and/or increased plasma levels that can be utilized relatively immediately by the body, e.g., for energy production (e.g., as an alternative energy source to glucose). The presence of the S-beta-hydroxybutyrate mixed salt-acid component can modulate this effect compared to compositions enriched with the R-beta-hydroxybutyrate mixed salt-acid component to provide, for example, a more controlled, progressive and/or prolonged ketogenic effect.

As a further example, a racemic R, S- β -hydroxybutyrate mixed salt-acid composition may advantageously increase blood ketone body levels relatively rapidly, primarily through the R- β -hydroxybutyrate enantiomer component, and further increase blood ketone body levels relatively more permanently, persistently, primarily through the S- β -hydroxybutyrate enantiomer component. Such compositions are thus capable of effectively and relatively rapidly assisting in inducing ketosis in a subject while providing sustained and prolonged delivery of ketone bodies to the blood stream, wherein the R- β -hydroxybutyrate and S- β -hydroxybutyrate components together provide a synergistic ketogenic benefit to the subject.

In contrast to compositions that intentionally minimize or eliminate S-beta-hydroxybutyrate, the racemic R, S-beta-hydroxybutyrate mixed salt-acid composition contains equal amounts of the S-beta-hydroxybutyrate enantiomer that is not endogenously produced by the mammal in order to produce one or more desired effects in the mammal. For example, administration of a combination of an S- β -hydroxybutyrate component with an R- β -hydroxybutyrate may result in at least one of the following: (1) increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; (2) endogenous transformation of the S- β -hydroxybutyrate component to one or both of R- β -hydroxybutyrate and acetoacetate; (3) endogenous conversion of the S- β -hydroxybutyrate component to fatty acids and sterols; (4) prolongation of ketosis; (5) the metabolism of the S- β -hydroxybutyrate component is independent of conversion to R- β -hydroxybutyrate and/or acetoacetate; (6) increased fetal development; (7) the growth years are increased; (8) decreased endogenous acetone production during ketosis; (9) the signaling of S-beta-hydroxybutyrate regulates the metabolism of R-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11) production of acetyl-CoA.

The racemic R, S- β -hydroxybutyrate mixed salt-acid compositions can be used, for example, to produce one or more desired effects in a subject, including but not limited to appetite suppression, weight loss, fat loss, reduced blood glucose levels, improved mental alertness, increased physical performance, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduction in cancer, reduction in inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.

In some embodiments, the racemic R, S- β -hydroxybutyrate mixed salt-acid composition may include or be combined with a carrier, such as a dietetic or pharmaceutically acceptable carrier. Examples of carriers or forms of the composition include powders, liquids, tablets, capsules, foods, food additives, beverages, vitamin-fortified beverages, beverage additives, candies, sippy, lozenges, food supplements, sprays, injections, and suppositories.

Examples of salts of R, S-beta-hydroxybutyrate include salts of alkali metals, alkaline earth metals, transition metals, amino acids or amino acid metabolites. 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, and the like, glutamine salts, and sarcosine salts.

The racemic R, S- β -hydroxybutyrate mixed salt-acid compositions can optionally include racemic R, S- β -hydroxybutyrate, such as mono-, di-, tri-, oligo-and polyesters. Examples include monoesters of ethanol, monoesters of 1-propanol, monoesters of 1, 2-propanediol, diesters of 1, 2-propanediol, monoesters of 1, 3-propanediol, diesters of 1, 3-propanediol, monoesters of S-, R-, or S-R-1, 3-butanediol, diesters of S-, R-, or S-R-1, 3-butanediol, monoglycerides, (3S) -hydroxybutyl (3S) -hydroxybutyrate monoesters, (3R) -hydroxybutyl (3S) -hydroxybutyrate monoesters, diglycerides, triglycerides, acetoacetates, diesters, triesters, oligoesters, and polyesters comprising repeating units of beta-hydroxybutyrate, and complex oligomers or polymers of BHB, and one or more other hydroxycarboxylic acids (e.g., lactic acid, and lactic acid, Citric acid, acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaric acid and malic acid), and/or beta-hydroxybutyrate and/or one or more diols (e.g. 1, 3-propanediol and 1, 3-butanediol), one or more polyacids (e.g. tartaric acid, citric acid, malic acid, succinic acid and fumaric acid), and short chain fatty acids, such as butyric acid, valeric acid or caproic acid.

In some embodiments, the composition may further comprise or be combined with at least one short chain fatty acid or at least one mono-, di-, or triglyceride of a short chain fatty acid, wherein the short chain fatty acid has less than 6 carbons. Examples of short chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid. An example of a short chain triglyceride is tributyrin. These molecules can protect the intestinal tract and improve microbial health.

The composition may comprise or be combined with at least one medium chain fatty acid or at least one mono-, di-or triglyceride of a medium chain fatty acid, wherein the medium chain fatty acid has from 6 to 12 carbons, preferably from 8 to 10 carbons. Exemplary medium chain fatty acids are caproic acid, caprylic acid, capric acid and lauric acid. Medium Chain Triglycerides (MCT), medium chain fatty acids, and mono-and diglycerides are ketone body precursors and can provide an additional source for the production of ketone bodies independent of R-beta-hydroxybutyrate.

The composition may comprise or be combined with at least one long chain fatty acid having more than 12 carbons or at least one mono-, di-or triglyceride of a long chain fatty 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.

Examples and sources of medium chain fatty acids or esters thereof (e.g., medium chain triglycerides) include coconut oil, coconut milk powder, fractionated coconut oil, palm kernel oil, caprylic acid, capric acid, isolated medium chain fatty acids (e.g., isolated caproic acid, isolated caprylic acid, isolated capric acid), medium chain triglycerides in purified or native form (e.g., coconut oil), and ester derivatives of medium chain fatty acid ethoxylated triglycerides, ketene triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives, and triglyceride derivatives, and salts of medium chain triglycerides. Ester derivatives optionally include alkyl ester derivatives such as methyl, ethyl, propyl, butyl, hexyl and the like.

Administration of a racemic mixture of the R- β -hydroxybutyrate mixed salt-acid component and the S- β -hydroxybutyrate mixed salt-acid component results in a dual effect, providing both: (1) initial and relatively immediate elevation in blood levels of ketone bodies; and (2) a later and relatively prolonged rise in blood levels of ketone bodies, thereby taking advantage of the metabolic and physiological advantages of (1) rapidly induced and (2) temporally sustained ketosis.

Increasing the levels of ketone bodies in the blood by exogenous supplementation provides the subject with greater dietary flexibility than methods that induce and maintain ketosis based solely on diet (e.g., based on fasting and/or limited carbohydrate intake). For example, a subject who has been administered an appropriate amount of a racemic mixture of the R- β -hydroxybutyrate mixed salt-acid component and the S- β -hydroxybutyrate mixed salt-acid component will be able to occasionally eat a carbohydrate or sugar-based food without compromising the ketogenic state and switching back to a glucose-based metabolic state. In addition, such administration facilitates easier conversion to the ketogenic state while reducing or eliminating the deleterious effects typically associated with entry ketosis.

In some embodimentsThe ketogenic composition further comprises a therapeutically effective amount of vitamin D₃. Vitamin D₃It is believed to promote good bone health and prevent undesirable calcification of soft tissue, along with magnesium and calcium. In a preferred embodiment, vitamin D is included₃In such an amount that the average daily dose of the ketogenic composition comprises from about 200IU ("international unit") to about 8000IU, or from about 400IU to about 4000IU, or from about 600IU to about 3000IU of vitamin D₃. In some embodiments, vitamin D is included₃In such an amount that the average daily dose of the ketogenic composition comprises from about 5 μ g to about 200 μ g, or from about 10 μ g to about 100 μ g, or from about 15 μ g to about 75 μ g of vitamin D₃。

Some embodiments further comprise one or more additional ketone precursors or supplements. These additional ketone precursors or supplements may include acetoacetic acid, ketone esters, and/or other compounds that result in elevated blood ketone levels without increasing electrolytes in the blood. Acetoacetate esters can be provided in salt form, ester form, acid form, and combinations thereof. Other additives include metabolites that enhance the action or transport of ketone bodies into mitochondria, caffeine, theobromine, and nootropic agents, such as L-alpha glycerophosphocholine ("alpha GPC").

The composition may include a flavoring agent that helps to mask the occasional off-taste of the beta-hydroxybutyrate compound (particularly when provided in non-salt form). These flavoring agents include essential oils (e.g., peppermint), natural and artificial sweeteners, and other flavoring agents known in the art.

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

Stack of racemic R, S-beta-hydroxybutyrate compounds

As noted above, the racemic R, S- β -hydroxybutyrate mixed salt-acid compositions described herein can be provided in three general forms: (1) racemic R, S- β -hydroxybutyrate, (2) racemic R, S- β -hydroxybutyrate, and optionally (3) racemic R, S- β -hydroxybutyrate. The compositions described herein may be provided in the form of a "stacked" mixture that combines at least the salt and acid forms and optionally the ester form

Each of these different forms has its own characteristics and potential benefits and limitations. For example, the ester form of beta-hydroxybutyrate generally has inferior organoleptic properties relative to other forms of beta-hydroxybutyrate. That is, the ester form of beta-hydroxybutyrate is generally described as having a harsh taste and/or odor.

The salt form of racemic R, S- β -hydroxybutyrate is generally considered to be more palatable than the ester form. However, administration of a clinically or dietetically effective dose of racemic R, S- β -hydroxybutyrate in salt form inherently requires administration of relatively high levels of the corresponding cation. For example, sodium is often used as the cation in beta-hydroxybutyrate, with high levels of sodium having a well-known negative health impact. Although different beta-hydroxybutyrate salts with different cations can be mixed to dilute the effects of a single cation, it is still difficult to provide an effective amount of beta-hydroxybutyrate without disrupting the electrolyte balance in the subject/patient.

Thus, the free acid form of racemic R, S- β -hydroxybutyrate (i.e. racemic R, S- β -hydroxybutyrate) is used to form mixed salt-acid compositions. Since β -hydroxybutyrate has a pKa of 4.70, it will deprotonate and produce H at physiological pH⁺. The resulting excess acidity can lead to undesirable side effects, including causing or exacerbating gastrointestinal problems such as ulceration or reflux.

Selecting a combined amount of the different forms of racemic R, S- β -hydroxybutyrate may advantageously limit the occurrence and/or severity of these adverse side effects and/or may allow for the administration of higher doses of the β -hydroxybutyrate compound. For example, a stack of beta-hydroxybutyrate can deliver the same amount of beta-hydroxybutyrate in a single form without the same and/or severe side effects occurring. Likewise, the combination form can deliver greater amounts of beta-hydroxybutyrate than the single form until a similar incidence and/or severity of side effects is achieved.

This is schematically illustrated in fig. 1A and 1B. Figure 1A shows different beta-hydroxybutyrate dosages when single form (formulations 1-3), double stack (formulations 4-6) and triple stack (formulation 7) were used. Although individual tolerability may vary, and thus the dosages shown are merely exemplary, a typical subject will wish to avoid an excess of any single form of beta-hydroxybutyrate, to avoid the corresponding side effects. Thus, stacking the different forms of beta-hydroxybutyrate allows for greater delivery of beta-hydroxybutyrate in the dose and/or allows for a higher frequency of administration than if a single form were used. For example, different forms of beta-hydroxybutyrate may be stacked in a single dose to allow for a greater amount of beta-hydroxybutyrate in the dose and/or different forms of beta-hydroxybutyrate may be taken at different doses throughout the day to allow for a greater frequency of administration to increase the total daily delivery of beta-hydroxybutyrate.

Figure 1B shows the expected relative severity of adverse side effects caused by treatment with various β -hydroxybutyrate formulations, including stacked formulations. A three-stack formulation comprising each of 1) the beta-hydroxybutyrate form, 2) the beta-hydroxybutyrate free acid form (i.e. beta-hydroxybutyrate), and 3) the beta-hydroxybutyrate form is expected to allow for the administration of greater amounts of beta-hydroxybutyrate and/or have reduced side effects compared to a two-stack comprising only two such beta-hydroxybutyrate forms. Triple stacking (i.e., tri-racemic stacking) and double stacking (i.e., double-racemic stacking) are also expected to allow for administration of greater amounts of beta-hydroxybutyrate and/or have reduced side effects compared to a single form comprising only one form of beta-hydroxybutyrate.

In other words, for a given dose of beta-hydroxybutyrate, the bi-racemic and tri-racemic stacks can be formulated to cause less 1) sensory side effects, 2) electrolyte imbalance side effects, and/or 3) acidity side effects than the single form. For example, a single form of beta-hydroxybutyrate may have a threshold dose not exceeded by the average user due to negative sensory side effects, a single form of beta-hydroxybutyrate may have a threshold dose limited by the recommended dietary restrictions of the electrolyte administered with the salt, and a single form of beta-hydroxybutyrate may have a threshold dose not exceeded by the average user due to negative effects of acidity. The stacked form of beta-hydroxybutyrate allows for greater amounts of beta-hydroxybutyrate to be replenished without exceeding any individual thresholds associated with sensory, electrolyte or acidity side effects.

In some embodiments, the beta-hydroxybutyrate stack includes at least two of: (i) one or more salts of R, S-beta-hydroxybutyrate; (ii) r, S- β -hydroxybutyric acid; and (iii) one or more beta-hydroxybutyrate esters. For example, the dual stack of beta-hydroxybutyrate can comprise at least two of components (i), (ii) and (iii), each component being provided in a range of from about 2% to about 98%, or from about 5% to about 95%, or from about 10% to about 90%, or from about 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60% based on the moles of beta-hydroxybutyrate.

An exemplary triple stack of beta-hydroxybutyrate comprises from about 2% to about 96%, or from about 5% to about 90%, or from about 10% to about 80%, or from about 20% to about 60% beta-hydroxybutyrate based on moles of beta-hydroxybutyrate, and comprises from about 2% to about 96%, or from about 5% to about 90%, or from about 10% to about 80%, or from about 20% to about 60% beta-hydroxybutyrate based on moles of beta-hydroxybutyrate. In some embodiments, the three stack of beta-hydroxybutyrate includes substantially equal amounts of each of the three forms of beta-hydroxybutyrate, based on moles of beta-hydroxybutyrate.

Stacked beta-hydroxybutyrate compositions may also provide a more beneficial digestive release profile. The interaction of each of the different forms of beta-hydroxybutyrate upon ingestion may be somewhat different. For example, the free acid form can be readily delivered to the bloodstream as a usable ketone body, beta-hydroxybutyrate from the salt form typically requires a slightly longer time to reach the bloodstream depending on the solubility characteristics of the particular salt or mixture of salts used, while beta-hydroxybutyrate from the ester form typically requires the longest time to reach the bloodstream depending on the rate of hydrolysis of the ester bond. Thus, stacked β -hydroxybutyrate formulations can be tailored to provide more preferred release profiles, for example formulations that combine the benefit of faster onset with the benefit of longer release, and/or formulations that provide an overall greater area under the curve for pharmacokinetics (AUC). The stacked compositions can provide timed delivery or availability of ketone bodies, which provides a more uniform blood concentration of ketone bodies and a significantly longer "tail" of delivery of exogenous ketone bodies, e.g., 1-8 hours after consumption of the stacked compositions.

This is shown in fig. 2, which fig. 2 compares the expected release profile of a ketone stacking composition (e.g., comprising a free acid and a salt) to each of the free acid, salt, and ester single forms. Because the ketone stacking compositions can provide more overall exogenous ketone bodies, and because they are provided in a variety of different forms having different release characteristics, the overall release profile is extended and provides a greater AUC.

Figure 2 also illustrates how the release profile can be adjusted by using different relative amounts of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate. As shown, the beta-hydroxybutyrate in the "R stack" consists of R-beta-hydroxybutyrate, while the "R/S stack" comprises a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, which flattens and lengthens the release profile.

Combination supplement

The ketogenic compositions described herein may advantageously be combined with one or more other dietetically and/or pharmaceutically acceptable supplements/drugs to form a combined supplement. The unique properties of the racemic R, S-beta-hydroxybutyrate mixed salt-acid composition can beneficially enhance the combination supplement compared to other similar combination supplements using a beta-hydroxybutyrate composition enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

For example, a composition intended to increase lipolysis and/or lipoxidation (referred to herein as a "fat burning agent" component) may be combined with a racemic R, S- β -hydroxybutyrate component to form a combined supplement with a synergistic lipolysis and/or fat burning effect. Without being bound by any particular theory, it is believed that the fat burning agent composition is easier to use when combined with the racemic R, S- β -hydroxybutyrate component than when the β -hydroxybutyrate component is not used. That is, the racemic R, S- β -hydroxybutyrate component can effectively "prime" the subject for more efficient metabolic utilization of lipids. As an energy source. For example, by exogenously supplementing a racemic R, S- β -hydroxybutyrate mixed salt-acid composition, a subject may increase the enzymes and other metabolic mechanisms necessary to utilize this ketone body (and stored body fat) as an energy source. Thus, when co-administered, the fat burning agent may have enhanced pharmacokinetics and/or pharmacodynamics, and thus may increase lipolysis and/or fat oxidation to a higher level than when the beta-hydroxybutyrate component or fat burning agent is administered alone.

These synergistic effects of the combination supplements are considered more pronounced when the beta-hydroxybutyrate component is the racemic R, S-beta-hydroxybutyrate component compared to when the R-beta-hydroxybutyrate or S-beta-hydroxybutyrate is enriched. This is schematically shown in fig. 3. As shown, for a given dosage of beta-hydroxybutyrate of the combination supplement, wherein the beta-hydroxybutyrate component is enriched in R-beta-hydroxybutyrate, the level of fat oxidation/lipolysis is initially relatively high but then gradually decreases relatively rapidly. When the beta-hydroxybutyrate component is enriched in S-beta-hydroxybutyrate, the level of fat oxidation/lipolysis is longer lasting than compositions enriched in R-beta-hydroxybutyrate, but the overall level of fat oxidation/lipolysis remains relatively low throughout.

On the other hand, where the beta-hydroxybutyrate component is racemic, the R-beta-hydroxybutyrate component and the S-beta-hydroxybutyrate component function to provide a relatively high initial level of fat oxidation/lipolysis and a relatively extended duration of fat oxidation/lipolysis. While it is possible that the racemic R, S- β -hydroxybutyrate version does not provide as high an initial level of fat oxidation/lipolysis as the enriched R- β -hydroxybutyrate version and may not provide as long a duration of fat oxidation/lipolysis as the enriched S- β -hydroxybutyrate version, the combined effect of the R- β -hydroxybutyrate component and the S- β -hydroxybutyrate component provides a higher overall level of fat oxidation/lipolysis when provided in an enantiomerically equivalent ratio. In other words, the area under the curve is greater when the racemic R, S- β -hydroxybutyrate composition is used in a combination supplement than when enriched R- β -hydroxybutyrate or enriched S- β -hydroxybutyrate.

The fat burning agent component may include one or more compounds capable of promoting lipolysis and/or fat oxidation. For example, the fat burning agent component may include green tea, green tea extract (e.g., a composition comprising one or more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extract, Conjugated Linoleic Acid (CLA), tetradecylthioacetic acid (TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4- (4-hydroxyphenyl) butan-2-one, p-hydroxyacetone), ephedrine, synephrine (e.g., bitter orange extract), octopamine, 1, 3-dimethylpentanamine, norcochine, fucoxanthin, acetylcholine modulators and/or adenosine receptor antagonists (e.g., caffeine), nicotine, kokui leaf (e.g., tea, extracts, isolates, salts and free bases), Ursolic acid, clenbuterol, norepinephrine reuptake inhibitors (e.g., methamphetamine, tomoxetine), 7-oxodehydroepiandrosterone (i.e., 7-ketodhea), thyroid hormones (e.g., triiodothyronine), and combinations thereof.

The combination supplement may include a beta-hydroxybutyrate component and a component intended to enhance mental alertness, cognition and/or mood (referred to herein as a "mental" component). As with the fat burning agent embodiment, a greater synergistic nootropic effect is expected when the beta-hydroxybutyrate component is a racemic mixture rather than enriched in R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

Exemplary compounds that may be included in the nootropic component include catecholamine precursors (e.g., tyrosine, L-DOPA (i.e., L-3, 4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP)), exemestanes (e.g., piracetam, oxiracetam, and aniracetam), L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors (e.g., damine and tomoxetine), ginseng (Panax ginseng), gingko biloba (Ginko biloba), Rhodiola (Rhodiola rosea), Polygala tenuilia (Polygala tenuilia), Muira puama (Muira puama), Papaver californicus (Escholzia californica), Convolvulus prandinaceae (Convolvululus pluricius), Centella asiatica (Centaria asiatica), Eupatorium (Epimeria) and Epimeria pseudonarcissus (Epimeria pseudonarum), Epimedium purpureum (Epimedes), and combinations thereof, Sophora africana herbs (Ashwagandha herbs), adenosine cyclic phosphate (cAMP) modulators (e.g., forskolin), stimulants (e.g., nicotine, caffeine, and amphetamine), cholinergic compounds and/or acetylcholine modulators (e.g., huperzine A, dimethylaminoethanol, choline, and alpha-glycerophosphocholine), and combinations thereof.

A combination supplement utilizing a racemic R, S- β -hydroxybutyrate component may include other supplements/drugs in addition to or as a substitute for the fat burning agent component. For example, the combination supplement may include one or more compounds for helping one or more of suppress appetite, reduce weight, reduce blood glucose levels, increase mental alertness, increase physical strength, improve cognitive function, reduce traumatic brain injury, reduce the effects of diabetes, improve neurological disorders, reduce cancer, reduce inflammation, resist aging, resist glycation, reduce seizures, improve mood, increase strength, increase muscle mass, or improve body composition.

In some embodiments, the ketogenic composition may include or be administered with other vitamin and/or mineral supplements (such as vitamin D3) and glucose control supplements (such as berberine) and other hypoglycemic substances. It is speculated that the racemic mixture of the mixed hydrochloride-acid components of R-and S- β -hydroxybutyrate may provide a more sustained hypoglycemic effect with other substances.

V. application

In some embodiments, the compositions disclosed herein can be used in a method of increasing ketone body levels (including promoting and/or maintaining ketosis) in a subject comprising 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 increased ketone body levels in a subject include promoting and/or maintaining ketosis, including one or more of appetite suppression, weight loss, fat loss, decreased blood glucose levels, improved mental alertness, increased physical performance, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduction in cancer, reduction in inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition in a subject.

In some embodiments, administration of a racemic mixture of R- β -hydroxybutyrate mixed salt-acid component and S- β -hydroxybutyrate mixed salt-acid component provides for one or more increased endogenous production of R- β -hydroxybutyrate and acetoacetate; endogenously converting the S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetoacetate; endogenously converting the S-beta-hydroxybutyrate component to fatty acids and sterols; prolonged ketosis; the metabolism of the S- β -hydroxybutyrate component is independent of conversion to R- β -hydroxybutyrate and/or acetoacetate; increased fetal development; the growth years are increased; decreased endogenous acetone production during ketosis; signaling of S-beta-hydroxybutyrate modulates the metabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-coenzyme a.

The ketogenic compositions described herein 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 or unit dose will include a total amount of the R- β -hydroxybutyrate component and S- β -hydroxybutyrate component from about 0.5g to about 25g, or from about 0.75 g to about 20 g, or from about 1 g to about 15 g, or from about 1.5 g to about 12 g.

The term "unit dose" refers to a dosage form configured to deliver a specific amount or dose of a composition or component thereof. Exemplary dosage forms include, but are not limited to, tablets, capsules, powders, foodstuffs, food additives, beverages (e.g., flavored, vitamin fortified, or non-alcoholic), beverage additives (e.g., flavored, vitamin fortified, or non-alcoholic), confections, sippers, lozenges, food supplements, dietetically acceptable sprays (e.g., flavored oral sprays), injections (e.g., non-alcoholic injections), and suppositories. Such dosage forms may be configured to provide a complete unit dose or fraction thereof (e.g., 1/2, 1/3, or 1/4 of a unit dose).

Another dosage form that may be used to provide a unit dose of the composition or a component thereof is a unit dose measuring device, such as a cup, spoon, syringe, dropper, spoon, spatula, or colon irrigation device, configured to hold therein a measured amount of the composition equal to the entire unit dose or a fraction thereof (e.g., 1/2, 1/3, or 1/4 of the unit dose). For example, a bulk container, such as a carton, box, can, jar, bag, bottle, jug, or keg, containing several unit doses of the composition (e.g., 5-250 or 10-150 unit doses) may be provided to a user along with a unit dose measuring device configured to provide a unit dose or fraction thereof of the composition or a component thereof.

A kit for providing a composition as disclosed herein in bulk form, while providing a unit dose of the composition, can include a bulk container containing a quantity of the composition therein and a unit dose measuring device configured to provide a unit dose or fraction thereof of the composition or a component thereof. One or more unit dose measuring devices may be located within the bulk container at the time of sale, connected to the exterior of the bulk container, pre-packaged with the bulk container in a larger package, or one or more bulk containers provided for use by the seller or manufacturer.

The kit may include instructions for the size of the unit dose or fraction thereof, as well as the mode and frequency of administration. The instructions may be provided on the bulk container, pre-packaged with the bulk container, placed on packaging material sold with the bulk container, or otherwise provided by the seller or manufacturer (e.g., on a website, mail, leaflet, product literature, etc.). The instructions may include a reference to how to properly deliver the unit dose or fraction thereof using the unit dose measurement device. The instructions may additionally or alternatively include reference to conventional unit dose measuring devices, such as spoons, spatulas, cups, etc., which are not provided with the bulk container (e.g., in the event that the provided unit dose measuring device is lost or misplaced). In such a case, the end user may construct the kit upon following instructions provided on or with the bulk container, or otherwise provided by the vendor, regarding the product and how to properly deliver the unit dose of the composition or a portion thereof.

The ketogenic composition may include or be administered with other supplements, such as vitamin D₃Vitamins, minerals, nootropic agents and other supplements known in the art. Examples of vitamins, minerals and herbal supplements that may 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, theophylline, taxotere, huperzine a, epicatechin, and enzymes.

The subject preferably follows a ketogenic diet that limits carbohydrate and protein intake during administration of the composition. In an exemplary embodiment, the subject may limit dietary intake to a ratio of about 65% fat, about 25% protein, and about 10% carbohydrate. The resulting therapeutic ketosis provides rapid and sustained ketoadaptation as a metabolic therapy for a wide range of metabolic diseases and nutritional support for therapeutic fasting, weight loss and performance enhancement. Thus, the compositions are typically administered once daily, twice daily, or three times daily to a subject in whom promotion and/or maintenance of ketosis status is desired.

In a preferred embodiment, the ketogenic composition may be administered orally in solid and/or powder form, for example in powder mixtures (e.g., powder-filled gelatin capsules), hard compressed tablets or other oral routes of administration known to those skilled in the art, in one or more unit doses per day.

Although oral administration is preferred, other routes of administration may additionally or alternatively be used. For example, some embodiments may be administered as an injection (e.g., subcutaneously, parenterally, or intravenously). Injections may include one or more of mannitol, 1, 3-butanediol, propylene glycol, water, ringer's solution, isotonic sodium chloride solution or other suitable dispersing or wetting agents and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid or cremastrin.

Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols which are solid at ordinary temperatures but liquefy, soften and/or dissolve at body temperature in the rectal cavity to release the supplement.

Exemplary compositions for nasal or pulmonary administration (e.g., aerosols or inhalants provided by heat or by nebulization) include saline solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents known in the art.

In some embodiments, multiple doses of the composition are administered over a period of time. The frequency of administration of the composition can vary depending on any of a variety of factors, such as the time of treatment from the start of a previous treatment, the purpose of the treatment, and the like. The duration of administration of the composition (e.g., the period of time 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, and the like.

The amount of the composition to be administered may vary depending on factors such as the sensitivity of the individual, the age, sex and weight of the individual, the specific response of the individual, and the like. The "therapeutically effective amount" is that amount necessary to promote a therapeutically effective result (i.e., therapeutic ketosis) in vivo. In accordance with the present disclosure, a suitable single dose size is a dose that is capable of preventing or alleviating (reducing or eliminating) symptoms in a patient when administered one or more times over a suitable period of time.

The amount of the composition administered will depend on the potency, absorption, distribution, metabolism, and excretion rate of the unused ketone bodies, electrolytes, methods of administration and the particular condition being treated, as well as other factors known to those skilled in the art. The dosage should be sufficient to affect a desired response, e.g., a therapeutic or prophylactic response to a particular disorder or condition, in view of the severity of the disorder to be alleviated. The compounds may be administered once, or may be administered separately and at intervals. It is to be understood that administration can be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

VI. examples

Described below are exemplary racemic mixtures of R- β -hydroxybutyrate and S- β -hydroxybutyrate, as well as other ketogenic compositions useful for increasing ketone levels in a subject, including inducing and maintaining a ketogenic state in a subject to which they are administered. It is to be understood that the beta-hydroxybutyrate compounds described in the examples can be in the form of salts, esters, dimers, trimers, oligomers and polymers as described herein. From the perspective of the examples, it is important that the enantiomeric percentages or ratios of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. The composition may include a mixture of R, S-beta-hydroxybutyrate and free R, S-beta-hydroxybutyrate to provide the desired electrolyte balance, taste and/or pharmacokinetic response. In some cases, the composition may be a mixture of salts, acids, and esters to provide the desired electrolyte balance and/or modulation of ketosis. The compositions may also be combined with short, medium or long chain fatty acids, esters, glycerides and other supplements disclosed herein to provide the desired level of elevated ketone bodies and other effects.

Example 1

A racemic R, S- β -hydroxybutyrate mixed salt-acid composition by combining one or more R- β -hydroxybutyrate compounds, one or more S- β -hydroxybutyrate compounds, R- β -hydroxybutyrate, and S- β -hydroxybutyrate to provide a 50% enantiomeric equivalent of the R- β -hydroxybutyrate mixed salt-acid component and a 50% enantiomeric equivalent of the S- β -hydroxybutyrate mixed salt-acid component. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition contains less than 100 mole equivalent% racemic R, S-beta-hydroxybutyrate and greater than 0 mole equivalent% free racemic R, S-beta-hydroxybutyrate.

Because the racemic mixture contains 50% enantiomeric equivalents of the R- β -hydroxybutyrate mixed hydrochloride-acid compound, the incidence of ketosis at a given dose is accelerated compared to the same dose enriched with the S- β -hydroxybutyrate compound. On the other hand, since the racemic mixture contains 50% of the enantiomeric equivalent of the S- β -hydroxybutyrate mixed hydrochloride compound, the duration of the persistent ketosis for a given dose is increased compared to the same dose enriched with the R- β -hydroxybutyrate compound.

The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition is readily administered as a ketogenic composition, for example in powder form as a dietary supplement mixed with food or beverages, in the form of one or more capsules or tablets, or in liquid form (e.g. oral spray).

Example 2

The racemic R, S- β -hydroxybutyrate mixed salt-acid composition of example 1 is formulated to provide 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% molar equivalents of racemic R, S- β -hydroxybutyrate, 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%, and less than 25%, 8%, 15%, 6%, 5%, 3%, or 3% molar equivalents of racemic R, 1.5%, 1.65%, 1.8%, 2%, or 3%, s-beta-hydroxybutyric acid.

Example 3

Example 1 or example 2 was modified by combining the racemic R, S- β -hydroxybutyrate mixed hydrochloride-acid composition with a dietetic (i.e. nutritional) or pharmaceutically acceptable carrier.

Example 4

Any of the foregoing embodiments are improved upon by combining the racemic R, S- β -hydroxybutyrate mixed salt-acid composition with one or more short chain fatty acids and/or one or more mono-, di-or triglycerides thereof (e.g. tributyrin).

Example 5

Any of the foregoing embodiments are improved by combining a racemic R, S- β -hydroxybutyrate mixed salt-acid composition with one or more medium chain fatty acids and/or one or more mono-, di-or triglycerides thereof (such as MCT oil).

Example 6

Any of the foregoing embodiments are improved by combining a racemic R, S- β -hydroxybutyrate mixed salt-acid composition with one or more long chain fatty acids and/or one or more mono-, di-or triglycerides thereof.

Example 7

By mixing a salt-acid composition with racemic R, S-beta-hydroxybutyrate in combination with one or more supplements (such as vitamin D)₃Vitamins, minerals), and other combinations of materials known in the art to improve upon any of the foregoing embodiments.

Example 8

By mixing a salt-acid composition with racemic R, S- β -hydroxybutyrate one or more fat burning supplements such as green tea, green tea extracts (e.g., compositions comprising one or more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extracts, Conjugated Linoleic Acid (CLA), Tetradecyl Thioacetic Acid (TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4- (4-hydroxyphenyl) butan-2-one, p-hydroxyacetone), ephedrine, synephrine (e.g., bitter orange extract), octopamine, 1, 3-dimethylpentanamine, norcochine, fucoxanthin, acetylcholine modulators and/or adenosine receptor antagonists (e.g., caffeine), Any of the foregoing embodiments are improved by combining nicotine, coca leaf derivatives, ursolic acid, clenbuterol, norepinephrine reuptake inhibitors (e.g., methamphetamine, tomoxetine), 7-oxodehydroepiandrosterone (i.e., 7-ketodhea), thyroid hormones (e.g., triiodothyronine), and combinations thereof.

The resulting combined supplement is expected to provide greater lipolytic and/or lipoxidative effects than similar dosages using the beta-hydroxybutyrate component enriched with R-beta-hydroxybutyrate or enriched with S-beta-hydroxybutyrate.

Example 9

By mixing the racemic R, S- β -hydroxybutyrate salt-acid composition with one or more nootropic supplements (e.g., tyrosine, L-DOPA (i.e., L-3, 4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP)), estanes (e.g., piracetam, oxiracetam, and aniracetam), L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors (e.g., damine and tomoxetine), ginseng, ginkgo biloba, rhodiola rosea, polygala tenuifolia, muira puamauroides, poppy californica, Convolvulaceae, centella asiatica, Evolvulus, Bacopa monniera, Epimedium, Nanfevia solanum herb, cyclic adenosine monophosphate (cAMP) modulators (e.g., forskolin), stimulants (e.g., nicotine, D-P), L-D-A-D-A, Caffeine and amphetamines), cholinergic compounds and/or acetylcholine modulators (such as huperzine a, dimethylaminoethanol, choline, and alpha-glycerophosphocholine), and combinations thereof, to improve upon any of the foregoing embodiments.

The resulting combination supplement is expected to provide better cognitive, alertness, and/or emotional benefits compared to similar dosages using the beta-hydroxybutyrate component enriched with R-beta-hydroxybutyrate or enriched with S-beta-hydroxybutyrate.

The present invention may 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. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

1. A racemic R, S- β -hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject comprising:

a racemic mixture of beta-hydroxybutyrate containing 50% enantiomeric equivalents of R-beta-hydroxybutyrate and 50% enantiomeric equivalents of S-beta-hydroxybutyrate; and

a racemic mixture of beta-hydroxybutyrate comprising 50% enantiomeric equivalents of one or more R-beta-hydroxybutyrate and 50% enantiomeric equivalents of one or more S-beta-hydroxybutyrate, wherein the beta-hydroxybutyrate is selected from:

sodium R-beta-hydroxybutyrate;

potassium R-beta-hydroxybutyrate;

calcium R-beta-hydroxybutyrate;

magnesium R-beta-hydroxybutyrate;

sodium S- β -hydroxybutyrate;

potassium S- β -hydroxybutyrate;

calcium S- β -hydroxybutyrate; and

magnesium S-beta-hydroxybutyrate;

wherein the composition is in solid and/or powder form.

2. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, wherein said composition comprises at least two of:

a racemic mixture of sodium R, S- β -hydroxybutyrate;

a racemic mixture of potassium R, S- β -hydroxybutyrate;

a racemic mixture of calcium R, S- β -hydroxybutyrate;

a racemic mixture of magnesium R, S- β -hydroxybutyrate.

3. A racemic R, S-beta-hydroxybutyrate mixed hydrochloride-acid composition according to either claim 1 or 2 wherein said composition comprises from 75% to 99.9% molar equivalent of the racemic mixture of beta-hydroxybutyrate and from 25% to 0.1% molar equivalent of the racemic mixture of beta-hydroxybutyrate.

4. A racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-3 wherein said composition comprises 80% to 99.7% molar equivalent of the racemic mixture of beta-hydroxybutyrate and 20% to 0.3% molar equivalent of the racemic mixture of beta-hydroxybutyrate.

5. A racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-4, wherein said composition comprises from 85% to 99.5% molar equivalent of the racemic mixture of beta-hydroxybutyrate and 15% to 0.5% molar equivalent of the racemic mixture of beta-hydroxybutyrate.

6. A racemic R, S-beta-hydroxybutyrate mixed salt-acid composition as claimed in any one of claims 1-5 wherein said composition comprises from 90% to 99% molar equivalents of the racemic mixture of beta-hydroxybutyrate and from 10% to 1% molar equivalents of the racemic mixture of beta-hydroxybutyrate.

7. The racemic R, S- β -hydroxybutyrate mixed salt-acid composition of any one of claims 1-6 further comprising at least one short chain fatty acid having less than 6 carbons, or at least one mono-, di-, or triglyceride of a short chain fatty acid.

8. The racemic R, S- β -hydroxybutyrate mixed salt-acid composition of any one of claims 1-7 further comprising at least one medium chain fatty acid having 6-12 carbons, such as 8-10 carbons, or a mono-, di-, or triglyceride of said at least one medium chain fatty acid.

9. The racemic R, S- β -hydroxybutyrate mixed salt-acid composition of any one of claims 1-8, further comprising at least one of:

a fat burning agent supplement for increasing lipolysis and/or fat oxidation; or

A mental supplement for improving cognitive ability, alertness and/or mood.

10. The racemic R, S- β -hydroxybutyrate mixed salt-acid composition of claim 9, wherein said one or more fat burning agent supplements are selected from the group consisting of: green tea, green tea extract, isolated green tea catechin, epigallocatechin gallate (EGCG), green coffee extract, Conjugated Linoleic Acid (CLA), tetradecylthioacetic acid (TTA), coleus forskohlii, yohimbine, rauwolscine, capsaicin, raspberry ketone, 4- (4-hydroxyphenyl) butan-2-one, p-hydroxyphenylacetone, ephedrine, synephrine, octopamine, 1, 3-dimethylpentylamine, norcoclaurine, fucoxanthin, acetylcholine modulators and/or adenosine receptor antagonists, caffeine, nicotine, coca leaf derivatives, ursolic acid, clenbuterol, noradrenaline reuptake inhibitors, hordenine, tomoxetine, 7-oxydrolepiandrosterone, triiodothyronine, and combinations thereof.

11. The racemic R, S- β -hydroxybutyrate mixed salt-acid composition of claim 9 or 10, wherein said one or more nootropic compounds is selected from the group consisting of: tyrosine, L-DOPA, tryptophan, 5-hydroxytryptophan, cetanos, piracetam, oxiracetam, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors, hordenine, tomoxetine, ginseng, ginkgo biloba, rhodiola rosea, polygala tenuifolia, muira puama, California poppy, Convolvulaceae Convolvula, centella asiatica, Evolvulus, Bacopa monnieri, Epimedium, African nightshade herb, cyclic adenosine monophosphate (cAMP) modulators, forskolin, nicotine, caffeine, amphetamine, coca derivatives, cholinergic compounds, acetylcholine modulators, huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine, and combinations thereof.

12. The racemic R, S- β -hydroxybutyrate mixed hydrochloride-acid composition of any one of claims 1-11, further comprising a racemic mixture of one or more R- β -hydroxybutyrate and one or more S- β -hydroxybutyrate.

13. A racemic R, S- β -hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject comprising:

sodium R-beta-hydroxybutyrate;

potassium R-beta-hydroxybutyrate;

calcium R-beta-hydroxybutyrate;

magnesium R-beta-hydroxybutyrate;

sodium S- β -hydroxybutyrate;

potassium S- β -hydroxybutyrate;

calcium S- β -hydroxybutyrate; and

magnesium S-beta-hydroxybutyrate;

wherein said composition is provided in the form of a tablet, capsule, powder, food additive, flavored beverage, vitamin-fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin-fortified beverage additive, non-alcoholic beverage additive, candy, drink or drink, lozenge, food supplement, flavored oral spray or suppository.

14. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 13, wherein said composition comprises from 75% to 99.9% molar equivalent of the racemic mixture of beta-hydroxybutyrate and from 25% to 0.1% molar equivalent of the racemic mixture of beta-hydroxybutyrate.

15. A racemic R, S- β -hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject comprising:

a dietetically or pharmaceutically acceptable carrier selected from the group consisting of tablets, capsules, powders, foods, food additives, flavored drinks, vitamin-fortified drinks, non-alcoholic drinks, flavored drink additives, vitamin-fortified drink additives, non-alcoholic drink additives, candies, sippy, lozenges, food supplements, flavored mouth sprays, and suppositories;

sodium R-beta-hydroxybutyrate;

potassium R-beta-hydroxybutyrate;

calcium R-beta-hydroxybutyrate;

magnesium R-beta-hydroxybutyrate;

sodium S- β -hydroxybutyrate;

potassium S- β -hydroxybutyrate;

calcium S- β -hydroxybutyrate; and

magnesium S-beta-hydroxybutyrate.

16. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 15, wherein said composition comprises from 75% to 99.9% molar equivalent of the racemic mixture of beta-hydroxybutyrate and from 25% to 0.1% molar equivalent of the racemic mixture of beta-hydroxybutyrate.

17. A kit for administering ketone bodies to a subject, comprising:

the racemic R, S- β -hydroxybutyrate mixed salt-acid composition of any one of claims 1-16;

a container for holding the composition; and

a measurement device configured to hold a unit dose of the composition or a fraction thereof therein, wherein the unit dose of the composition comprises from about 0.5g to about 25g of the R- β -hydroxybutyrate compound.

18. The kit of claim 17, wherein the container is selected from the group consisting of: cartons, boxes, cans, jars, bags, bottles, kettles and kegs.

19. The kit of claim 17 or 18, wherein the measuring device is selected from the group consisting of: cup, ladle, syringe, burette, spatula, ladle and colon washing unit.

20. A method for increasing ketone body levels in a subject comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of the composition of claim 1, wherein

Increasing ketone body levels in the subject results in one or more of: appetite suppression, weight loss, fat loss, reduced blood glucose levels, improved mental alertness, anxiolytic effect (anxiolytic), faster response time, increased physical performance, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduction in cancer, reduction in inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition; and

the S- β -hydroxybutyrate component of the composition results in at least one of:

increased endogenous production of R- β -hydroxybutyrate and acetoacetate;

endogenous transformation of the S- β -hydroxybutyrate component to one or both of R- β -hydroxybutyrate and acetoacetate;

endogenous conversion of the S- β -hydroxybutyrate component to fatty acids and sterols;

prolongation of ketosis;

the metabolism of the S- β -hydroxybutyrate component is independent of conversion to R- β -hydroxybutyrate and/or acetoacetate;

increased fetal development;

the growth years are increased;

decreased endogenous acetone production during ketosis;

modulating the metabolism of R-beta-hydroxybutyrate and glucose through signaling of the S-beta-hydroxybutyrate component;

antioxidant activity; or

Production of acetyl CoA.