Racemic beta-hydroxybutyrate mixed hydrochloride-acid composition and kit

Abstract

To provide racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions and kits for use in increasing ketone body levels in a subject.SOLUTION: Ketogenic compositions include a racemic mixture of R- and S-beta-hydroxybutyric acids and a racemic mixture of R- and S-beta-hydroxybutyrate salts. The compositions contain a R-enantiomer to elevate ketone bodies and increase a rate at which ketosis is achieved and yet contain an equivalent amount of a S-enantiomer to provide alternative benefits. The R- and S-beta-hydroxybutyric acids are more rapidly absorbed and utilized by a body than salts or esters, enhance a taste, and reduce need to include a citric acid or other edible acids. The R- and S-beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and can provide one or more electrolytes.SELECTED DRAWING: None

Description

Technical Field

[0001] This specification discloses the use of racemic beta-hydroxybutyrate compounds, particularly salts and acids of racemic beta-hydroxybutyrate, and racemic beta-hydroxybutyrate mixed salt-acid compound compositions for raising the blood levels of ketone bodies in a subject.

Background Art

[0002] During periods of fasting, intense exercise, and / or low carbohydrate consumption, the body's glucose and glycogen stores can be rapidly depleted. Failure to replenish glucose stores associated with their depletion causes the body to metabolically shift to using ketone bodies for energy ( "ketosis"). Ketone bodies can be used by the body's cells as fuel to meet the body's energy demands, including the demands 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 the primary 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, that is, during ketogenic metabolism in the liver, the body uses dietary fat and body fat as the primary 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 state of ketone production, essentially burning fat as its primary fuel source. Fat is broken down into fatty acids and glycerol, the fatty acids are converted into acetyl-CoA molecules, and these acetyl-CoA molecules are ultimately converted in the liver through ketone production into water-soluble ketone bodies: beta-hydroxybutyrate (i.e., "β-hydroxybutyrate" or "BHB"), acetacetate (also known as acetylacetonate), and acetone. Beta-hydroxybutyrate and acetacetate are the main ketone bodies used as energy in the body, while acetone is removed and excreted as a byproduct of ketone production.

[0005] Ketone body metabolism is associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle-preserving properties, and improved cognitive and physical abilities. The science-based improvements in cellular metabolic efficiency managed by ketone supplementation have beneficial effects on physical, cognitive, and psychological health, and may have long-term impacts on health related to common preventable diseases such as obesity, cardiovascular disease, neurodegenerative diseases, diabetes, and cancer.

[0006] While pursuing a ketogenic diet and lifestyle and maintaining a state of nutritional ketosis offers numerous health benefits, significant obstacles remain in pursuing and maintaining a ketogenic state. One of these obstacles is the difficulty of entering a ketogenic state. The fastest endogenous way to enter ketosis is through depletion of glucose stores in the body via fasting combined with exercise. This is physically and mentally demanding and extremely difficult, even for the most motivated and disciplined individuals.

[0007] Furthermore, the transition to ketosis is often accompanied by hypoglycemia, which can frequently cause lethargy and dizziness, resulting in an unpleasant physical and mental state commonly known as "low-carb flu." Many people also experience metabolic downregulation as the body naturally enters an "energy-saving" mode. Some believe these transient symptoms can last for as long as two to three weeks. If a person consumes a meal or snack containing more carbohydrates than the limit during this transition period, ketone production will immediately cease, and the body will exit ketosis. The body will then return to using glucose as its primary fuel, and the transition to ketosis will have to be restarted.

[0008] If a subject successfully establishes ketosis, maintaining it is equally difficult, if not extremely difficult, because it requires strictly maintaining the ratio of carbohydrates and proteins to fats in the diet. This is further complicated by the disruption of normal electrolyte balance that often occurs when transitioning to and maintaining a ketogenic state. Depletion and reduction of glycogen stores in the liver and muscles reduces the body's ability to retain water, leading to increased urination and, consequently, greater electrolyte loss. Additionally, the decrease in insulin levels due to ketosis can affect the rate at which certain electrolytes are excreted by the kidneys, potentially further lowering electrolyte levels in the body. Negative effects of electrolyte imbalance include muscle pain, cramps, spasms and weakness, restlessness, anxiety, frequent headaches, extreme thirst, insomnia, fever, palpitations or irregular heartbeat, gastrointestinal symptoms (such as sudden abdominal pain, constipation, or diarrhea), confusion and difficulty concentrating, bone disorders, joint pain, changes in blood pressure, changes in appetite or weight, fatigue (including chronic fatigue syndrome), numbness in the joints, and dizziness (especially when standing up suddenly).

[0009] Several compositions used to promote ketosis in mammals include those by Lowery et al., disclosed in U.S. Patent Application Publication 2017 / 0296501, which contain the endogenous form of beta-hydroxybutyrate, i.e., R-beta-hydroxybutyrate, while Lowery et al. do not recommend the use of non-endogenous enantiomers or S-beta-hydroxybutyrate, or racemic mixtures of R- and S-beta-hydroxybutyrate. Other compositions, such as those disclosed by Clarke et al. in U.S. Patent 8,642,654, consist mostly or entirely of a single beta-hydroxybutyrate ester (3R)-hydroxybutyl(3R)-hydroxybutyrate. 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] U.S. Patent Application Publication No. 2017 / 0296501 [Patent Document 2] U.S. Patent No. 8,642,654 [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] (overview) This specification discloses racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid compositions and methods of use for increasing ketone body levels in a subject, including promoting and / or sustaining ketosis in the subject over a long period of time. [Means for solving the problem]

[0012] The racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions disclosed herein include a racemic mixture of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt ("R,S-beta-hydroxybutyrate salt") and a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate ("R,S-beta-hydroxybutyrate"). The "racemic mixture" of R,S-beta-hydroxybutyrate salt contains enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyrate salt. The "racemic mixture" of R,S-hydroxybutyrate contains enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyrate.

[0013] R-beta-hydroxybutyrate is an endogenous form produced by mammals, while S-beta-hydroxybutyrate enters the body through exogenous supplementation via the administration of a racemic RS-beta-hydroxybutyrate mixed hydrochloride-acid composition. Thus, although the racemic RS-beta-hydroxybutyrate mixed hydrochloride-acid composition contains separate components with different functions in the body, it provides an enhanced ketogenic effect, including more sustained blood ketone levels, compared to the administration of R-beta-hydroxybutyrate compounds alone. The R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition provides at least a "double racemic stack" of beta-hydroxybutyrate compounds.

[0014] R-beta-hydroxybutyrate enantiomers are endogenously produced by mammals during ketosis; therefore, exogenously administered R-beta-hydroxybutyrate hydrochloride-acid components provide additional amounts of R-beta-hydroxybutyrate and / or increased plasma levels that can be immediately utilized by the body, such as for energy production (e.g., as an alternative energy source to glucose). S-beta-hydroxybutyrate components, which are not endogenously produced by mammals, complement the R-beta-hydroxybutyrate components and provide mammals with one or more desired effects that are not produced by the R-beta-hydroxybutyrate components alone.

[0015] For example, by administering the S-beta-hydroxybutyrate mixed hydrochloride-acid component together with the R-beta-hydroxybutyrate mixed hydrochloride-acid component in an enantiomerically equivalent ratio, (1) an increase in the endogenous production of R-beta-hydroxybutyrate and acetacetate, (2) endogenous conversion of the S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetacetate, (3) endogenous conversion of the S-beta-hydroxybutyrate component to fatty acids and sterols, ( At least one of the following is obtained: 4) prolongation of ketosis, (5) metabolism of the S-beta-hydroxybutyrate component independent of conversion to R-beta-hydroxybutyrate and / or acetacetate, (6) increased fetal growth, (7) increased years of growth, (8) decreased endogenous production of acetone during ketosis, (9) signaling by the S-beta-hydroxybutyrate component that modulates the metabolism of R-beta-hydroxybutyrate and glucose, (10) antioxidant activity, and (11) acetyl-CoA production.

[0016] Exogenous delivery of a racemic R,S-beta-hydroxybutyrate hydrochloride (R-hydroxybutyrate) hydrochloride composition can beneficially provide a relatively more sustained increase in blood ketone body levels, primarily due to the S-beta-hydroxybutyrate hydrochloride component, as well as a relatively rapid increase in blood ketone body levels, primarily due to the R-beta-hydroxybutyrate hydrochloride component, particularly R-beta-hydroxybutyrate. Such a racemic R,S-beta-hydroxybutyrate hydrochloride composition can effectively and relatively rapidly induce ketosis in the target population, while simultaneously delivering ketone bodies into the bloodstream in a sustained and long-term manner through the modulating effect of the S-beta-hydroxybutyrate hydrochloride component, providing the ketogenic effects the body requires.

[0017] Combining R,S-beta-hydroxybutyrate with one or more R,S-beta-hydroxybutyrate salts is highly beneficial because it reduces electrolyte load, increases absorption, improves taste, facilitates formulation, and reduces the need to add citric acid or other edible acids to obtain compositions with a neutral or acidic pH.

[0018] In some embodiments, the racemic R,S-beta-hydroxybutyrate hydrochloride-acid compositions described herein may be combined with one or more other food- and / or pharmaceutically acceptable supplements / drugs (e.g., by direct mixing or in combination administration) to form a combination supplement. The unique properties of the racemic R,S-beta-hydroxybutyrate hydrochloride-acid compositions can beneficially enhance combination supplements compared to other similar combination supplements that use beta-hydroxybutyrate compositions consisting of either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate, or enriched with either. For example, a composition intended to enhance lipolysis and / or fat oxidation (referred herein to as a “fat burner” component) may be combined with the racemic R,S-beta-hydroxybutyrate hydrochloride-acid composition to form a combination supplement having a synergistic lipolysis and / or fat-burning effect. In another example, a composition intended to enhance mental arousal, cognition, and / or mood (referred to herein as “nootropic” components) may be combined with a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition to form a combination supplement having synergistic cognitive, arousal, and / or mood-enhancing effects.

[0019] In some embodiments, the racemic R,S-beta-hydroxybutyrate hydrochloride-acid compositions disclosed herein may be used in methods for increasing ketone body levels in a subject (including promoting and / or maintaining ketosis in the subject), which include administering one or more of the compositions disclosed herein in nutritionally or pharmaceutically effective amounts to a subject in need of administration. Examples of beneficial effects of increasing ketone body levels in a subject include one or more of the following: appetite suppression, weight loss, fat loss, decreased blood glucose levels, improved mental agility, anxiety relief (anxiolytic), reduced response time, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neuropathy, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased physical strength, increased muscle mass, or improved body composition.

[0020] The composition may contain a nutritionally or pharmaceutically acceptable carrier.

[0021] Embodiments include the "racemic stacking" of at least four different beta-hydroxybutyrate compounds. R-beta-hydroxybutyrate and S-beta-hydroxybutyrate provide the free acids (i.e., R-beta-hydroxybutyric acid and S-beta-hydroxybutyric acid), their salts (i.e., R-beta-hydroxybutyrate salts and S-beta-hydroxybutyrate salts), and optionally their esters (i.e., R-beta-hydroxybutyrate esters and S-beta-hydroxybutyrate esters). Providing beta-hydroxybutyrate as a double racemic stack (or a triple racemic stack combining six separate forms) that combines at least four separate forms of beta-hydroxybutyrate advantageously allows for the use of a greater amount of beta-hydroxybutyrate for a given dosage and / or may allow for a greater dosage per day. Each form of beta-hydroxybutyrate is typically associated with its own specific positive properties and negative side effects. Stacking different forms of beta-hydroxybutyrate can provide more positive properties compared to using each alone. Similarly, stacking different forms of beta-hydroxybutyrate can reduce or mitigate the negative side effects of each specific form of beta-hydroxybutyrate and "disperse" and limit such negative effects. In either case, stacking increases or maximizes the overall dosage of beta-hydroxybutyrate that can be effectively delivered.

[0022] That is, the present invention provides the following.

[0023] The present invention is a racemic R,S-beta-hydroxybutyrate mixed salt-hydrochloric acid composition for increasing ketone levels in a subject, a racemic mixture of beta-hydroxybutyric acid comprising 50% R-beta-hydroxybutyric acid in enantiomeric equivalents and 50% S-beta-hydroxybutyric acid in enantiomeric equivalents, and, A racemic mixture of beta-hydroxybutyrate salts comprising one or more R-beta-hydroxybutyrate salts at an enantiomeric equivalent of 50% and one or more S-beta-hydroxybutyrate salts at an enantiomeric equivalent of 50%, wherein the beta-hydroxybutyrate salts are Sodium R-beta-hydroxybutyrate, Potassium R-beta-hydroxybutyrate, Calcium R-beta-hydroxybutyrate, Magnesium R-beta-hydroxybutyrate, Sodium S-beta-hydroxybutyrate, Potassium S-beta-hydroxybutyrate, Calcium S-beta-hydroxybutyrate, and Magnesium S-beta-hydroxybutyrate, selected from, a racemic mixture, Provided is a racemic R,S-beta-hydroxybutyrate mixed salt-hydrochloric acid composition in which the composition is in solid and / or powder form, Preferably, the composition is A racemic mixture of R,S-beta-hydroxybutyrate sodium, A racemic mixture of R,S-beta-hydroxybutyrate potassium, A racemic mixture of R,S-beta-hydroxybutyrate calcium, or A racemic mixture of R,S-beta-hydroxybutyrate magnesium, containing at least two of Preferably, the composition contains a racemic mixture of beta-hydroxybutyrate salts in a molar equivalent of 75% to 99.9% and a racemic mixture of beta-hydroxybutyric acid in a molar equivalent of 25% to 0.1%. Preferably, the composition contains a racemic mixture of beta-hydroxybutyrate salts in a molar equivalent of 80% to 99.7% and a racemic mixture of beta-hydroxybutyric acid in a molar equivalent of 20% to 0.3%. Preferably, the composition comprises a racemic mixture of 85% to 99.5% by molar equivalent of beta-hydroxybutyrate salt and a racemic mixture of 15% to 0.5% by molar equivalent of beta-hydroxybutyric acid. Preferably, the composition comprises a racemic mixture of 90% to 99% by molar equivalent of beta-hydroxybutyrate salt and a racemic mixture of 10% to 1% by molar equivalent of beta-hydroxybutyric acid. Preferably, further comprising at least one short-chain fatty acid having fewer than six carbon atoms, or a mono-, di-, or triglyceride of the at least one short-chain fatty acid. Preferably, the material further comprises at least one medium-chain fatty acid having 6 to 12 carbon atoms, for example, 8 to 10 carbon atoms, or a mono-, di-, or triglyceride of the at least one medium-chain fatty acid. Preferably, a fat burner supplement to increase lipolysis and / or fatty acid conversion, Further comprising at least one of the following: cognitive ability, attention, and / or mood-enhancing nootropic supplements, Preferably, one or more of the fat burner 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), tetradecylthioacetate (TTA), Coleus forskohlii, yohimbine, rauwaruscin, capsaicin, raspberry ketone, 4-(4-hydroxyphenyl)butan-2-one, p-hydroxybenzylacetone, ephedrine, synephrine, octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulators and / or adenosine receptor antagonists, caffeine, nicotine, coca leaf extract, ursolic acid, clenbuterol, norepinephrine reuptake inhibitors, hordenine, atomoxetine, 7-oxodehydroepiandrosterone, triiodothyronine, and combinations thereof. Preferably, at least one of the nootropic compounds is tyrosine, L-DOPA, tryptophan, 5-hydroxytryptophan, racetam, piracetam, oxyracetam, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitor, hordenine, atomoxetine, ginseng (Panax ginseng), ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvulus pluricaulis, Centella asiatica, Evolvulus Selected from the group consisting of alsinoides, Bacopa monnieri, Epimedium herb, Ashwagandha herb, cyclic adenosine monophosphate (cAMP) modulator, forskolin, nicotine, caffeine, amphetamine, coca leaf extract, cholinergic compounds, acetylcholine modulator, huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine, and combinations thereof. Preferably, the mixture further comprises a racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters.

[0024] The present invention relates to a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition for increasing ketone levels in a subject, A racemic mixture of beta-hydroxybutyric acid containing 50% R-beta-hydroxybutyric acid by enantiomer equivalent and 50% S-beta-hydroxybutyric acid by enantiomer equivalent, and A racemic mixture of beta-hydroxybutyrate salts comprising one or more R-beta-hydroxybutyrate salts in an enantiomer equivalent of 50% and one or more S-beta-hydroxybutyrate salts in an enantiomer equivalent of 50%, wherein the beta-hydroxybutyrate salts are R-Beta-hydroxybutyrate sodium, R-beta-hydroxybutyrate potassium, R-Beta-hydroxybutyrate calcium, R-Beta-hydroxybutyrate magnesium, S-beta-hydroxybutyrate sodium, S-beta-hydroxybutyrate potassium, S-beta-hydroxybutyrate calcium, and, A racemic mixture selected from S-beta-hydroxybutyrate magnesium, The present invention provides a racemic R,S-beta-hydroxybutyrate mixed hydrochloric acid composition which is provided as or contained within 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, lollipops, lozenges, nutritional supplements, flavored mouth sprays, or suppositories, Preferably, the composition comprises a racemic mixture of 75% to 99.9% by molar equivalent of beta-hydroxybutyrate salt and a racemic mixture of 25% to 0.1% by molar equivalent of beta-hydroxybutyric acid.

[0025] The present invention relates to a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition for increasing ketone levels in a subject, Food- or pharmaceutically acceptable carriers 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, lollipops, lozenges, dietary supplements, flavored mouth sprays, and suppositories. A racemic mixture of beta-hydroxybutyric acid containing 50% R-beta-hydroxybutyric acid by enantiomer equivalent and 50% S-beta-hydroxybutyric acid by enantiomer equivalent, and A racemic mixture of beta-hydroxybutyrate salts comprising one or more R-beta-hydroxybutyrate salts in an enantiomer equivalent of 50% and one or more S-beta-hydroxybutyrate salts in an enantiomer equivalent of 50%, wherein the beta-hydroxybutyrate salts are R-Beta-hydroxybutyrate sodium, R-beta-hydroxybutyrate potassium, R-Beta-hydroxybutyrate calcium, R-Beta-hydroxybutyrate magnesium, S-beta-hydroxybutyrate sodium, S-beta-hydroxybutyrate potassium, S-beta-hydroxybutyrate calcium, and We provide a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition comprising a racemic mixture selected from S-beta-hydroxybutyrate magnesium, Preferably, the composition comprises a racemic mixture of 75% to 99.9% by molar equivalent of beta-hydroxybutyrate salt and a racemic mixture of 25% to 0.1% by molar equivalent of beta-hydroxybutyric acid.

[0026] The present invention is a kit for administering ketone bodies to a subject, The above-mentioned racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition of the present invention, The container in which the composition is placed, and A measuring device configured to hold a unit dose or fraction of the composition, wherein the unit dose of the composition contains about 0.5 g to about 25 g of the R-beta-hydroxybutyrate compound. A kit is provided that includes, Preferably, the container is selected from the group consisting of cartons, boxes, cans, jars, bags, pouches, bottles, pitchers, and barrels. Preferably, the kit according to claim 17 or 18, wherein the measuring device is selected from the group consisting of a cup, a scoop, a syringe, a dropper, a spatula, a spoon, and a colon irrigation device.

[0027] The present invention provides a method for increasing ketone body levels in a subject, comprising administering a nutritionally or pharmaceutically effective amount of the composition of the present invention to a subject in need of administration, wherein An increase in ketone body levels in the aforementioned subjects results in one or more of the following: appetite suppression, weight loss, fat loss, decreased blood glucose levels, improved mental agility, anxiety reduction (anxiolytic effect), reduced response time, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neuropathy, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased physical strength, increased muscle mass, or improved body composition, and The S-beta-hydroxybutyrate component in the above composition is Increased endogenous production of R-beta-hydroxybutyrate and acetacetate. Endogenous conversion of the S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetacetate, Endogenous conversion of the aforementioned S-beta-hydroxybutyrate component to fatty acids and sterols, Extension of ketosis, Metabolism of the S-beta-hydroxybutyrate component, independent of conversion to R-beta-hydroxybutyrate and / or acetacetate, Increased fetal development, Increase in the number of years of growth, Decreased endogenous production of acetone during ketosis. Signal transduction by the S-beta-hydroxybutyrate component that regulates the metabolism of R-beta-hydroxybutyrate and glucose. Antioxidant activity, or, The present invention provides a method for causing at least one of the following: the production of acetyl-CoA.

[0028] Further features and advantages are described in part in the following description, some of which will become apparent from the description or can be acquired by performing the embodiments disclosed herein. It should be understood that both the brief summary above and the detailed description below are for illustrative and illustrative purposes only and are not intended to limit the embodiments or claims described herein. [Brief explanation of the drawing]

[0029] [Figure 1A] Figure 1A shows the higher levels of beta-hydroxybutyrate administered when using “stacked” doses of at least two different forms of racemic R,S-beta-hydroxybutyrate compared to a single form of racemic R,S-beta-hydroxybutyrate. [Figure 1B] Figure 1B shows the relative proportions of expected undesirable side effects resulting from treatment with various beta-hydroxybutyrate formulations, where "double-compound" (i.e., double racemic) formulations containing (1) free R,S-beta-hydroxybutyrate and (2) R,S-beta-hydroxybutyrate salt, as well as "triple-compound" (i.e., triple racemic) formulations containing R,S-beta-hydroxybutyrate ester in addition to the double-compound formulation, allow for the administration of larger amounts of beta-hydroxybutyrate and / or are expected to reduce the occurrence and severity of side effects compared to administering beta-hydroxybutyrate alone. [Figure 2]Figure 2 compares the expected release profiles of R,S-beta-hydroxybutyrate stacked compositions with those of the free acid, salt, and ester in their single forms, as well as the R,S-beta-hydroxybutyrate stacks, showing that the stacked R,S compositions have an overall elongated release profile and a larger area under the curve (AUC). [Figure 3] Figure 3 shows the expected relative ratio of lipolysis and / or fatty acidification as a result of treatment with a combination weight loss supplement containing beta-hydroxybutyrate and other weight loss supplements, and shows that the total amount of lipolysis and / or fatty acidification (area under the curve) is greater with the combination supplement using racemic R,S-beta-hydroxybutyrate compared to other similar combination supplements / medications using beta-hydroxybutyrate enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate. [Modes for carrying out the invention]

[0030] (Detailed explanation) 1.Definition The compound "beta-hydroxybutyrate," also known as β-hydroxybutyrate, 3-hydroxybutyrate, βHB, or BHB, is a deprotonated form of beta-hydroxybutyric acid, a hydroxycarboxylic acid with the general formula CH3CH2OHCH2COOH. The deprotonated form present at typical biological pH levels is CH3CH2OHCH2COO - The general chemical structures shown below represent beta-hydroxybutyrate compounds that may be used in the disclosed compositions. [ka] (In the formula, X may be hydrogen, a metal ion, an amino cation such as an amino acid, an alkyl, alkenyl, aryl, or acyl.

[0031] If X is hydrogen, the compound is beta-hydroxybutyrate. If X is a metal ion or an amino cation, the compound is a beta-hydroxybutyrate salt. If X is an alkyl, alkenyl, aryl, or acyl, the compound is a beta-hydroxybutyrate ester. The aforementioned compounds may be in any desired physical form, such as crystals, powders, solids, liquids, solutions, suspensions, or gels.

[0032] The term "racemic R,S-beta-hydroxybutyrate" means that the composition contains enantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate. The terms "racemic R,S-beta-hydroxybutyrate salt" and "racemic R,S-beta-hydroxybutyrate salt" mean that the composition contains enantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate salt. The term "racemic R,S-beta-hydroxybutyrate" means that the composition contains enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyrate. The terms "racemic R,S-beta-hydroxybutyrate ester" and "racemic R,S-beta-hydroxybutyrate ester" mean that the composition contains enantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate ester.

[0033] The term "R,S-beta-hydroxybutyrate mixed salt-acid composition" means that the composition contains enantiomerically equivalent amounts of one or more R-beta-hydroxybutyrate salts and one or more S-beta-hydroxybutyrate salts, and that the composition contains enantiomerically equivalent amounts (50:50) of free R-beta-hydroxybutyrate and free S-beta-hydroxybutyrate.

[0034] The term "R,S-beta-hydroxybutyrate salt" does not imply or suggest any particular physical state, such as crystals, powders, or other solid forms, that dissolve in water to form a solution or disperse in a liquid to form a suspension or gel. Salts may be formed in solution by, for example, at least partially neutralizing beta-hydroxybutyrate with alkali metal or alkaline earth metal hydroxides, carbonates, or bicarbonates, or with strong or weak bases such as basic amino acids.

[0035] The term "free beta-hydroxybutyrate" refers to the sum of un-deprotonated and deprotonated beta-hydroxybutyrate molecules. Deprotonated beta-hydroxybutyrate molecules generally refer to molecules that have released protons to form hydronium ions (H3O+) and beta-hydroxybutyrate anions (e.g., dissolved in water).

[0036] Free beta-hydroxybutyrate molecules, when present in a beta-hydroxybutyrate mixed hydrochloric acid composition in dry powder or other solid form, are typically not deprotonated to a significant degree. In such cases, the fractional amount of free beta-hydroxybutyrate in a beta-hydroxybutyrate mixed hydrochloric acid composition on a weight basis is the weight of free beta-hydroxybutyrate divided by the total weight of free beta-hydroxybutyrate and beta-hydroxybutyrate salt. On a molar basis, the fractional amount of free beta-hydroxybutyrate in a beta-hydroxybutyrate mixed hydrochloric acid composition is the molar equivalent of free beta-hydroxybutyrate divided by the total molar equivalent of free beta-hydroxybutyrate and beta-hydroxybutyrate anion provided by the beta-hydroxybutyrate salt.

[0037] When dissolved in water, a portion of beta-hydroxybutyrate typically dissociates into beta-hydroxybutyrate anions and hydronium ions (H3O+). As a result, beta-hydroxybutyrate molecules can exchange protons and cations with the dissolved beta-hydroxybutyrate salt. For the purpose of defining the relative amounts of beta-hydroxybutyrate and beta-hydroxybutyrate salt in a beta-hydroxybutyrate mixed-acid composition, the dissociation of beta-hydroxybutyrate molecules and the exchange of protons and cations are not understood to change the molar ratio of free beta-hydroxybutyrate to beta-hydroxybutyrate anions from the beta-hydroxybutyrate salt. The total amount of free beta-hydroxybutyrate molecules in solution is the sum of the dissolved beta-hydroxybutyrate molecules that have not been deprotonated and the beta-hydroxybutyrate anions formed by the deprotonation of the beta-hydroxybutyrate molecules.

[0038] In other words, the total molar equivalent of beta-hydroxybutyrate in solution is understood to be the difference between (i) the sum of the molar equivalents of undeprotonated beta-hydroxybutyrate molecules and the total molar equivalents of beta-hydroxybutyrate anions (from all sources) in solution, and (ii) the total molar equivalent of the 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), regardless of whether it is deprotonated or not. Alkali metal cations, such as sodium and potassium, provide 1 mole of cationic charge per mole of metal cation. On the other hand, alkaline earth metal cations, such as magnesium and calcium, provide 2 moles of cationic charge per mole of metal cation. One mole of deprotonated beta-hydroxybutyrate molecules provides 1 mole of anionic charge and 1 mole of cationic charge.

[0039] From the above, the mole fraction of beta-hydroxybutyrate in the solution relative to the total number of moles of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate 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 percentage in the solution.

[0040] For example, if a 100 molar equivalent of a beta-hydroxybutyrate mixed salt-acid composition in dry powder form contains 5% free, unprotonated beta-hydroxybutyrate and 95% beta-hydroxybutyrate salt on a molar basis, then substantially 5 molar equivalents of beta-hydroxybutyrate molecules and 95 molar equivalents of beta-hydroxybutyrate anions will be present. If there is enough water to dissolve the beta-hydroxybutyrate salt and some of the beta-hydroxybutyrate molecules are deprotonated, the molar equivalent of unprotonated beta-hydroxybutyrate will be less than 5, and the molar equivalent of beta-hydroxybutyrate anions will be greater than 95. The degree of deprotonation of beta-hydroxybutyrate in solution is related to pH.

[0041] Whether beta-hydroxybutyrate is an R-enantiomer or an S-enantiomer depends on the orientation of the hydroxyl tetrahedron on the 3-carbon (beta-carbon) in relation to the planar carboxyl group.

[0042] Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, an endogenous form produced by mammals, can be utilized by the patient's body as a fuel source when glucose levels are low in the subject, or when the patient's body receives supplementation with a usable form of beta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a "ketone body."

[0043] As used herein, “ketogenic composition” is formulated to increase ketone body levels in a subject, including inducing and / or sustaining a state in which ketone bodies are elevated to a desired level, such as ketosis, in the subject to which it is administered.

[0044] As used herein, “subject” or “patient” refers to members of the animal kingdom, including but not limited to mammals, including humans and other primates, rodents, fish, reptiles, and birds. The subject may be any animal in need of treatment, intervention, or prevention, or any animal suspected of needing treatment, intervention, or prevention. Prevention means taking action to prevent events that may occur, such as when high glucose or diabetes is present. “Patient” and “subject” are used interchangeably herein.

[0045] As used herein, “ketosis” refers to subjects in which blood ketone levels, including both enantiomers of β-hydroxybutyrate, acetacetate, and acetone, are in the range of approximately 0.5 mmol / L to approximately 16 mmol / L. Ketosis may improve mitochondrial function, reduce the production of reactive oxygen species, alleviate inflammation, and increase the activity of neurotrophic factors. As used herein, “keto adaptation” refers to long-term nutritional ketosis (>1 week) to achieve maintained, non-pathological “mild ketosis” or “therapeutic ketosis.”

[0046] In some cases, “elevated ketone levels” may not mean that the subject is in a state of “clinical ketosis,” but rather that there is an increased supply of ketones for energy production and / or for other beneficial effects of ketone metabolism and signaling. For example, a “ketone-adapted” subject may not necessarily have elevated serum ketone levels, but rather can utilize available ketones more rapidly than a non-ketone-adapted subject. In such cases, “elevated ketone levels” may refer to the total amount and / or proportion of ketones utilized by the subject, rather than the plasma level itself.

[0047] As used herein, the terms “administer” or “to administer” are used to describe the process of delivering the disclosed composition to the subject. The composition may be administered in a variety of ways, including, among others, orally, intragastricly, and parenterally (referring to intravenous and intra-arterial routes, as well as other suitable parenteral routes).

[0048] The term “combination supplement” is used herein to describe a combination of a beta-hydroxybutyrate component and 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, such as by mixing them together in the same tablet, capsule, mixed powder, or other dosage form, or by placing the separate components in the same packaging without direct mixing. However, in other embodiments, it is not necessary for the separate components to be directly combined before administration in order to fall within the scope of this disclosure. For example, separate components may be administered to a subject separately but within sufficiently close time intervals (e.g., within about 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours from each other) to be considered co-administered and therefore considered part of a “combination supplement.”

[0049] II. Racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition A composition for increasing ketone body levels in a subject, including promoting and / or sustaining ketosis, contains a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition comprising (1) one or more R-beta-hydroxybutyrate salts and multiple S-beta-hydroxybutyrate salts in 50% enantiomer equivalents, and (2) R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in 50% enantiomer equivalents. The composition may optionally contain one or more R-beta-hydroxybutyrate esters in 50% enantiomer equivalents and one or more S-beta-hydroxybutyrate esters in 50% enantiomer equivalents. A racemic mixture of R,S-beta-hydroxybutyrate mixed hydrochloride-acid components may produce synergistic effects when used in combination with other components. In such cases, the combined form of R,S-beta-hydroxybutyrate salt and acid has an acceptable pH and taste. R,S-beta-hydroxybutyrate mixed salt-acid compositions have substantial advantages over racemic R,S-beta-hydroxybutyrate salts and esters, including improved absorption, improved bioavailability, reduced electrolyte load, ease of manufacture, significantly improved taste, and reduced need for citric acid or other edible acids to obtain compositions with neutral or acidic pH.

[0050] In some embodiments, the racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition contains less than 100% racemic R,S-beta-hydroxybutyrate salt and more than 0% free racemic R,S-beta-hydroxybutyrate. The racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition contains 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%, and It may contain 97% total racemic R,S-beta-hydroxybutyrate salt 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% total free racemic R,S-beta-hydroxybutyrate. The aforementioned percentages are expressed on a molar basis (e.g., moles of free R,S-beta-hydroxybutyrate relative to the total moles of the R,S-beta-hydroxybutyrate compound in both salt and acid forms).

[0051] A racemic mixture of R-beta-hydroxybutyrate mixed hydrochloride-acid component and S-beta-hydroxybutyrate mixed hydrochloride-acid component contains equal amounts of the R-beta-hydroxybutyrate enantiomer, which is an endogenous form produced by mammals, and the S-beta-hydroxybutyrate enantiomer, which is not naturally produced or found in mammals, in order to enhance the ketogenic effect by delivering the R-beta-hydroxybutyrate enantiomer, which is produced by mammals, and the S-beta-hydroxybutyrate enantiomer, which is not naturally produced or found in mammals, either individually or in an enriched form.

[0052] For example, since the R-beta-hydroxybutyrate enantiomer is endogenously produced by mammals during ketosis, administering the R-beta-hydroxybutyrate mixed hydrochloride component to a target provides an additional amount that can be relatively immediately available in the body for purposes such as generating energy (e.g., as an alternative energy source to glucose), and / or increases plasma levels. The presence of the S-beta-hydroxybutyrate mixed hydrochloride component can modulate this effect to provide a more controlled, milder, and / or prolonged ketogenic effect compared to, for example, a composition enriched with the R-beta-hydroxybutyrate mixed hydrochloride component.

[0053] As a further example, racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid compositions can beneficially provide a relatively rapid boost to blood ketone levels, primarily through the R-beta-hydroxybutyrate enantiomer component, in addition to relatively prolonging and sustaining the increase in blood ketone levels mainly through the S-beta-hydroxybutyrate enantiomer component. Such compositions can effectively and relatively rapidly induce ketosis in the subject while simultaneously providing sustained and long-term delivery of ketones to the bloodstream, where the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate components work together to provide synergistic ketogenic benefits to the subject.

[0054] In contrast to compositions that intentionally minimize or eliminate S-beta-hydroxybutyrate, racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid compositions contain an equivalent amount of S-beta-hydroxybutyrate enantiomers not endogenously produced by mammals to produce one or more desired effects in mammals. For example, administration of an S-beta-hydroxybutyrate mixed hydrochloride-acid component together with an R-beta-hydroxybutyrate mixed hydrochloride-acid component may result in: (1) increased endogenous production of R-beta-hydroxybutyrate and acetacetate; (2) endogenous conversion of the S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetacetate; (3) endogenous conversion of the S-beta-hydroxybutyrate component to fatty acids and sterols; (4) prolongation of ketosis; (5 At least one of the following may be provided: (6) metabolism of the S-beta-hydroxybutyrate component independent of conversion to R-beta-hydroxybutyrate and / or acetacetate; (7) increased fetal growth; (8) decreased endogenous production of acetone during ketosis; (9) signaling by S-beta-hydroxybutyrate that modulates the metabolism of R-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11) production of acetyl-CoA.

[0055] Racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid compositions may be used to produce one or more desired effects in a subject, including, but are not limited to, appetite suppression, weight loss, fat reduction, lowering of blood glucose levels, improvement of mental agility, increased physical energy, improved 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, improved mood, increased physical strength, increased muscle mass, or improvement of body composition.

[0056] In some embodiments, the racemic R,S-beta-hydroxybutyrate hydrochloride-acid composition may include or be combined with a carrier, such as a food- 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, lollipops, lozenges, dietary supplements, sprays, injections, and suppositories.

[0057] Examples of R,S-beta-hydroxybutyrate salts 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, glutamine salts, and creatine salts.

[0058] The racemic R,S-beta-hydroxybutyrate mixed hydrochloric acid composition may optionally contain racemic R,S-beta-hydroxybutyrate esters such as mono-, di-, tri-, oligo-, and polyester. For example, monoester of ethanol, monoester of 1-propanol, monoester of 1,2-propanediol, diester of 1,2-propanediol, monoester of 1,3-propanediol, diester of 1,3-propanediol, monoester of S-, R-, or SR-1,3-butanediol, diester of S-, R-, or SR-1,3-butanediol, monoester of glycerin, monoester of (3S)-hydroxybutyl(3S)-hydroxybutyrate, monoester of (3R)-hydroxybutyl(3S)-hydroxybutyrate, diester of glycerin, triester of glycerin, acetone Examples include toacetate esters, dimers, trimers, oligomers, and polyesters having repeating units of BHB, as well as complex oligomers or polymers 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, one or more polyacids such as 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.

[0059] In some embodiments, the composition may further comprise, or be combined with, at least one short-chain fatty acid, or a mono-, di-, or triglyceride of at least one short-chain fatty acid, where the short-chain fatty acid has fewer than six carbon atoms. 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 triptyline. Such molecules can protect the gut and improve the health of the microbiome.

[0060] The composition may contain or be combined with at least one medium-chain fatty acid, or a mono-, di-, or triglyceride of the at least one medium-chain fatty acid, where the medium-chain fatty acid has 6 to 12 carbon atoms, preferably 8 to 10 carbon atoms. Examples of medium-chain fatty acids include caproic acid, caprylic acid, capric acid, and lauric acid. Medium-chain triglycerides (MCTs), medium-chain fatty acids, and mono- and di-glycerides are ketone body precursors that can provide an additional source for ketone body production independent of R-beta-hydroxybutyrate.

[0061] The composition may include, or be combined with, at least one long-chain fatty acid having more than 12 carbon atoms, or a mono-, di-, or triglyceride of the at least one 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.

[0062] Examples and sources of medium-chain fatty acids, or their esters, such as medium-chain triglycerides, include coconut oil, coconut milk powder, coconut oil, palm oil, palm kernel oil, caprylic acid, capric acid, isolated medium-chain fatty acids (isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid, etc.), any medium-chain triglycerides in their refined or natural form (such as coconut oil), and ester derivatives of medium-chain fatty acid ethoxylated triglycerides, enone triglyceride 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, and hexyl.

[0063] Administering a racemic mixture of R-beta-hydroxybutyrate mixed hydrochloride-acid component and S-beta-hydroxybutyrate mixed hydrochloride-acid component yields a dual effect that provides both: (1) an initial and relatively immediate increase in ketone body blood levels, and (2) a subsequent relatively prolonged increase in ketone body blood levels, allowing for the utilization of metabolic and physiological benefits such as (1) rapid induction of ketosis and (2) prolonged ketosis over time.

[0064] By increasing blood ketone body levels through exogenous supplementation, subjects gain greater flexibility in dietary choices compared to methods that aim to induce and maintain ketosis solely based on diet (e.g., fasting and / or carbohydrate restriction). For example, subjects administered a racemic mixture of appropriate amounts of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate hydrochloride components can occasionally consume carbohydrate or sugar-based foods without jeopardizing their ketogenic state or reverting to a glucose-based metabolic state. Furthermore, such administration facilitates the transition to ketosis and mitigates or eliminates the typical adverse effects associated with the transition to ketosis.

[0065] In some embodiments, the ketogenic composition further contains a therapeutically effective amount of vitamin D3. Vitamin D3 is thought to work together with magnesium and calcium to promote good bone health and prevent undesirable calcification of soft tissues. In preferred embodiments, the ketogenic composition contains vitamin D3 in an amount such that the average daily dose contains, for example, about 200 IU ("International Units") to about 8000 IU, or about 400 IU to about 4000 IU, or about 600 IU to about 3000 IU. In some embodiments, the ketogenic composition contains vitamin D3 in an amount such that the average daily dose contains, for example, about 5 μg to about 200 μg, or about 10 μg to about 100 μg, or about 15 μg to about 75 μg.

[0066] Some embodiments also include one or more additional ketone precursors or supplements. These additional ketone precursors or supplements may include acetacetates, ketone esters, and / or other compounds that cause an increase in blood ketone levels without adding more electrolytes to the bloodstream. Acetacetates may be provided in the form of salts, esters, acids, and combinations thereof. Other additives may include metabolites that enhance the effect or promote the transport of ketone bodies to the mitochondria, nootropes such as caffeine, theobromine, and L-alpha-glyceryl phosphorylcholine ("alpha-GPC").

[0067] The composition may also contain flavorings that help mask the occasional unpleasant taste of the beta-hydroxybutyrate compound (especially if provided in an unsalted form). These include essential oils such as peppermint, natural and artificial sweeteners, and other flavorings known in the art.

[0068] 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, fluidizers, and / or hygroscopic agents may be included in types and amounts safe for ingestion. Such additional components may include one or more of the following: 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.

[0069] III. Accumulation of racemic R,S-beta-hydroxybutyrate compounds As described above, the racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions described herein may be provided in three common forms: (1) racemic R,S-beta-hydroxybutyrate salt, (2) racemic R,S-beta-hydroxybutyrate, and optionally (3) racemic R,S-beta-hydroxybutyrate ester. The compositions described herein may be provided in “stacked” mixtures combining at least the salt and acid forms, and optionally the ester form.

[0070] Each of the different forms has its own characteristics and its own potential advantages and limitations. For example, the ester forms of beta-hydroxybutyrate typically have inferior sensory properties compared to other forms of beta-hydroxybutyrate. That is, the ester forms of beta-hydroxybutyrate are often described as having a pungent taste and / or smell.

[0071] The salt forms of racemic R,S-beta-hydroxybutyrate are generally considered to taste better than their ester forms. However, administering clinically or dietarily effective amounts of racemic R,S-beta-hydroxybutyrate in salt form requires the administration of relatively high levels of the corresponding cations. For example, sodium is often used as the cation in beta-hydroxybutyrate salts, and high levels of sodium are known to have adverse health effects. While mixing different beta-hydroxybutyrate salts with different cations can mitigate the effects of a single cation, providing an effective amount of beta-hydroxybutyrate without disrupting the electrolyte balance of the subject / patient remains challenging.

[0072] Therefore, the free acid form of racemic R,S-beta-hydroxybutyrate (i.e., racemic R,S-beta-hydroxybutyrate) is used to form mixed hydrochloric acid compositions. Since the pKa of beta-hydroxybutyrate is 4.70, it deprotonates at physiological pH and H +This generates excessive acidity, which can lead to undesirable side effects such as causing or worsening gastrointestinal problems like ulcers and reflux.

[0073] By combining selected amounts of different forms of racemic R,S-beta-hydroxybutyrate, the occurrence and / or severity of these undesirable side effects can be beneficially limited, and / or higher doses of beta-hydroxybutyrate compounds can be administered. For example, beta-hydroxybutyrate stacking can provide the same amount of beta-hydroxybutyrate as a single form, without causing the same occurrence and / or severity of side effects. Similarly, a combined form can provide a larger amount of beta-hydroxybutyrate than a single form before reaching a similar occurrence and / or severity of side effects.

[0074] This is schematically illustrated in Figures 1A and 1B. Figure 1A shows the dosages of various forms of beta-hydroxybutyrate when used in single form (formulations 1-3), double stacking (formulations 4-6), and triple stacking (formulation 7). Individual tolerances may vary, and therefore the illustrated dosages are illustrative only, however a typical subject would want to avoid an overdose of any single form of beta-hydroxybutyrate to avoid corresponding side effects. Thus, stacking different forms of beta-hydroxybutyrate allows for greater delivery of beta-hydroxybutyrate at a given dose and / or a higher dosing frequency compared to using a single form. For example, stacking different forms of beta-hydroxybutyrate at a single dose can increase the amount of beta-hydroxybutyrate at that dose, and / or taking different forms of beta-hydroxybutyrate at different doses throughout the day can increase the dosing frequency, resulting in a greater overall daily delivery of beta-hydroxybutyrate.

[0075] Figure 1B shows the expected relative severity of undesirable side effects resulting from treatment with various formulations of beta-hydroxybutyrate, including multiplying formulations. Triple-multiply formulations, each consisting of 1) a salt form of beta-hydroxybutyrate, 2) a free acid form of beta-hydroxybutyrate (i.e., beta-hydroxybutyrate), and 3) an ester form of beta-hydroxybutyrate, are expected to allow for the administration of larger amounts of beta-hydroxybutyrate and / or reduce side effects compared to double-multiply formulations consisting of only two such forms of beta-hydroxybutyrate. Both triple-multiply formulations (i.e., triple racemic formulations) and double-multiply formulations (i.e., double racemic formulations) are similarly expected to allow for the administration of larger amounts of beta-hydroxybutyrate and / or reduce side effects compared to single formulations consisting of only one form of beta-hydroxybutyrate.

[0076] In other words, for a given dose of beta-hydroxybutyrate, double and triple racemic stacks may be formulated to reduce 1) sensory side effects, 2) electrolyte imbalance side effects, and / or 3) acidity side effects compared to single forms. For example, a single form of beta-hydroxybutyrate ester may have a threshold dose that a typical user would not exceed due to negative sensory side effects, a single form of beta-hydroxybutyrate salt may have a threshold dose that is limited by recommended dietary restrictions on electrolytes administered with the salt, and a single form of beta-hydroxybutyrate may have a threshold dose that a typical user would not exceed due to adverse acidity effects. Stacked forms of beta-hydroxybutyrate allow for supplementation of larger amounts of beta-hydroxybutyrate without exceeding any of the separate thresholds associated with sensory, electrolyte, or acidity side effects.

[0077] In some embodiments, the beta-hydroxybutyrate stack comprises at least two of the following: (i) one or more R,S-beta-hydroxybutyrate salts, (ii) R,S-beta-hydroxybutyrate, and (iii) one or more beta-hydroxybutyrate esters. For example, the beta-hydroxybutyrate double stack may comprise at least two of components (i), (ii), and (iii), each provided in a molar base of about 2% to about 98%, or about 5% to about 95%, or about 10% to about 90%, or about 20% to about 80%, or about 30% to about 70%, or about 40% to about 60% of beta-hydroxybutyrate.

[0078] An exemplary beta-hydroxybutyrate triple stack comprises a beta-hydroxybutyrate ester in molar basis of about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% to about 60%, of beta-hydroxybutyrate; a beta-hydroxybutyrate salt in molar basis of about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% to about 60%, of beta-hydroxybutyrate; and beta-hydroxybutyrate in molar basis of about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% to about 60%, of beta-hydroxybutyrate. In some embodiments, the beta-hydroxybutyrate triple stack comprises each of the three forms of beta-hydroxybutyrate in substantially equal amounts in molar basis of beta-hydroxybutyrate.

[0079] Stacked beta-hydroxybutyrate compositions may also offer a more beneficial digestion-release profile. Each of the different forms of beta-hydroxybutyrate may interact somewhat differently upon ingestion. For example, the free acid form may be readily delivered to the bloodstream as an available ketone body, beta-hydroxybutyrate from salt forms may generally take slightly longer to reach the bloodstream depending on the solubility properties of the particular salt or salt mixture utilized, and beta-hydroxybutyrate from ester forms may generally take the longest to reach the bloodstream depending on the rate at which the ester bond undergoes hydrolysis. Thus, stacked beta-hydroxybutyrate formulations may be modified to offer a more favorable release profile, such as one that combines the benefits of a faster onset with the benefits of a longer release, and / or one that provides a larger overall area under the pharmacokinetic curve (AUC). The stacked composition can provide timed delivery or availability of ketone bodies, resulting in more uniform blood concentrations of ketone bodies and a significantly longer delivery "tail" of exogenous ketone bodies (e.g., 1-8 hours after consumption of the stacked composition).

[0080] This is illustrated in Figure 2, where the expected release profiles of keto stacking compositions (e.g., consisting of free acid and salt) are compared to those of the single forms of free acid, salt, and ester. Keto stacking compositions can provide a greater overall exogenous ketone body and, because they are provided in multiple different forms with different release properties, the overall release profile is extended, resulting in a larger AUC.

[0081] Furthermore, Figure 2 illustrates how the release profile can be adjusted by changing the relative amounts of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate. As shown in the figure, the beta-hydroxybutyrate in "R stacking" consists of R-beta-hydroxybutyrate, while "R / S stacking" contains a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, which flattens and lengthens the release profile.

[0082] IV. Combination Supplements The ketogenic compositions described herein may be beneficially combined with one or more other food- and / or pharmaceutically acceptable supplements / drugs to form combination supplements. The unique properties of the racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid compositions allow for beneficial enhancement of such combination supplements compared to other similar combination supplements using beta-hydroxybutyrate compositions enriched with either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

[0083] For example, a composition intended to increase lipolysis and / or fatty acid formation (referred to herein as a “fat burner” component) may be combined with a racemic R,S-beta-hydroxybutyrate component to form a combination supplement having a synergistic lipolysis and / or fat burning effect. Without being bound by any particular theory, it is thought that fat burner compositions are more readily available when combined with a racemic R,S-beta-hydroxybutyrate component than when used without the beta-hydroxybutyrate component. That is, the racemic R,S-beta-hydroxybutyrate component may function to effectively “prime” the subject to metabolically efficient utilization of lipids as an energy source. For example, by exogenously supplementing with a racemic R,S-beta-hydroxybutyrate hydrochloride-acid composition, it is thought that the subject will enhance the enzymes and other metabolic mechanisms necessary to utilize such ketone bodies (and thus stored body fat) as an energy source. Therefore, fat burners may enhance pharmacokinetics and / or pharmacodynamics, potentially promoting lipolysis and / or fatty acid synthesis at higher levels than when beta-hydroxybutyrate components or fat burners are administered alone.

[0084] These synergistic effects of combination supplements are thought to be more pronounced when the beta-hydroxybutyrate component is a racemic R,S-beta-hydroxybutyrate component, rather than being enriched with either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate. This is schematically illustrated in Figure 3. As shown, in the case of a combination supplement with a given beta-hydroxybutyrate dose in which the beta-hydroxybutyrate component is enriched with R-beta-hydroxybutyrate, the level of fatty acidation / lipolysis is relatively high at first, but then tapers off relatively quickly. When the beta-hydroxybutyrate component is enriched with S-beta-hydroxybutyrate, the level of fatty acidation / lipolysis lasts longer than in the enriched R-beta-hydroxybutyrate composition, but the overall level of fatty acidation / lipolysis remains relatively low overall.

[0085] On the other hand, when the beta-hydroxybutyrate component is a racemic mixture, the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate components function to provide relatively high initial levels of fatty acidification / lipolysis, as well as a relatively long duration of fatty acidification / lipolysis. The racemic R,S-beta-hydroxybutyrate version may not provide as high an initial level of fatty acidification / lipolysis as the enriched R-beta-hydroxybutyrate version, nor may it provide as long a duration of fatty acidification / lipolysis as the enriched S-beta-hydroxybutyrate version, but the combined effect of the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate components, when provided in enantiomerically equivalent proportions, results in a higher overall level of fatty acidification / lipolysis. In other words, when a racemic R,S-beta-hydroxybutyrate composition is used in a combination supplement, the area under the curve is larger compared to enriched R-beta-hydroxybutyrate or enriched S-beta-hydroxybutyrate.

[0086] The fat burner component may contain one or more compounds that can promote the enhancement of lipolysis and / or fatty acid formation. For example, the fat burner component may include green tea, green tea extract (e.g., a composition containing one or more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), and Coleus forskohlii. Examples include forskolin (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4-(4-hydroxyphenyl)butan-2-one, p-hydroxybenzylacetone), ephedrine, synephrine (e.g., bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulators and / or adenosine receptor antagonists (e.g., caffeine), nicotine, coca leaves (e.g., tea, extracts, isolates, salts, and free bases), ursolic acid, clenbuterol, norepinephrine reuptake inhibitors (e.g., hordenine, atomoxetine), 7-oxodehydroepiandrosterone (7-ketoDHEA), thyroid hormones (e.g., triiodothyronine), and combinations thereof.

[0087] The combination supplement may contain a beta-hydroxybutyrate component and a component intended to enhance mental arousal, cognition, and / or mood (referred to herein as the “nootropic” component). Similar to the fat burner embodiment, a greater synergistic nootropic effect is expected when the beta-hydroxybutyrate component is in a racemic mixture than when it is enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.

[0088] Examples of compounds that may be included in nootropic components include catecholamine precursors such as tyrosine, L-DOPA (L-3,4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP); racetams such as piracetam, oxyracetam, and aniracetam; norepinephrine reuptake inhibitors such as L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, hordenine, and atomoxetine; and plants such as Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvulus pluricaulis, and Centella asiatica. Examples include plants such as asiatica, morning glory (Evolvulus alsinoides), dwarf moss (Bacopa monnieri), epimedium herb, ashwagandha herb, cyclic adenosine monophosphate (cAMP) modulators such as forskolin, stimulants such as nicotine, caffeine, and amphetamines, cholinergic compounds such as huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine and / or acetylcholine modulators, and combinations thereof.

[0089] Combination supplements utilizing racemic R,S-beta-hydroxybutyrate components may include other supplements / medications in addition to, or as an alternative to, the fat burner component. For example, a combination supplement may include one or more compounds intended to assist in one or more of the following: appetite suppression, weight loss, reduction of blood glucose levels, improvement of mental agility, 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, increased physical strength, increase of muscle mass, or improvement of body composition.

[0090] In some embodiments, the ketogenic composition may include, or be administered together with, other vitamin and / or mineral supplements such as vitamin D3, as well as glucose control supplements such as berberine, and other glucose-lowering substances. A racemic mixture of R- and S-beta-hydroxybutyrate hydrochloride-acid components is hypothesized to provide a more sustained glucose-lowering effect in conjunction with other substances.

[0091] v. Administration In some embodiments, the compositions disclosed herein may be used in methods to increase ketone body levels in a subject, including promoting and / or maintaining ketosis, which comprises administering one or more of the compositions disclosed herein in nutritionally or pharmaceutically effective amounts to a subject in need of administration. Examples of beneficial effects of increasing ketone body levels in a subject, including promoting and / or maintaining ketosis, include one or more of the following: appetite suppression, weight loss, fat loss, decreased blood glucose levels, improved mental agility, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neuropathy, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased physical strength, increased muscle mass, or improved body composition.

[0092] In some embodiments, administration of a racemic mixture of R-beta-hydroxybutyrate mixed hydrochloride-acid component and S-beta-hydroxybutyrate mixed hydrochloride-acid component provides one or more of the following: increased endogenous production of R-beta-hydroxybutyrate and acetacetate; endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetacetate; endogenous conversion of S-beta-hydroxybutyrate component to fatty acids and sterols; prolongation of ketosis; metabolism of S-beta-hydroxybutyrate component independent of conversion to R-beta-hydroxybutyrate and / or acetacetate; increased fetal development; increased years of growth; decreased endogenous production of acetone during ketosis; signaling by S-beta-hydroxybutyrate that modulates the metabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-CoA.

[0093] The ketogenic compositions described herein may be administered to a subject in a therapeutically effective dose and / or at a frequency that induces or maintains ketosis. In some embodiments, a single dose or unit dose comprises the total amount of the R-beta-hydroxybutyrate component and the S-beta-hydroxybutyrate component, ranging from about 0.5 grams to about 25 grams, or about 0.75 grams to about 20 grams, or about 1 gram to about 15 grams, or about 1.5 grams to about 12 grams.

[0094] The term "unit dose" refers to a dosage form configured to deliver a specific amount or dose of a composition or component. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, foods, food additives, beverages (flavored, vitamin-fortified, or non-alcoholic, etc.), beverage additives (flavored, vitamin-fortified, or non-alcoholic, etc.), candies, lollipops, pastilles, dietary supplements, food-acceptable sprays (such as flavored mouth sprays), injections (such as alcohol-free injections), and suppositories. Such dosage forms may be configured to deliver a complete unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a unit dose).

[0095] 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 therein a measured amount of the composition equal to a full unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a unit dose). For example, bulk containers such as cartons, boxes, cans, jars, bags, pouches, bottles, pitchers, or small barrels containing several unit doses of a composition (e.g., 5 to 250 or 10 to 150 unit doses) may be provided to the user together with a unit dose measuring device configured to provide a unit dose or a fraction thereof of the composition or its components.

[0096] Kits used to provide compositions disclosed herein in bulk form and to provide unit doses of compositions may include a bulk container holding a certain amount of composition therein, and a unit dose measuring device configured to provide a unit dose or fraction thereof of the composition or its components. One or more unit dose measuring devices may be placed inside the bulk container at the time of sale, mounted on the outside of the bulk container, pre-packaged together with the bulk container in a larger package, or provided by the seller or manufacturer for use with one or more bulk containers.

[0097] The kit may include instructions regarding the size of the unit dose or fraction thereof, as well as the method and frequency of administration. These instructions may be printed on the bulk container, pre-packaged with the bulk container, placed in packaging sold with the bulk container, or provided by the seller or manufacturer (e.g., website, mailer, leaflet, product information). The instructions may include references to the use of a unit dose measuring device for appropriately dispensing the unit dose or fraction thereof. The instructions may additionally or alternatively include references to common unit dose measuring devices not included with the bulk container, such as spoons, spatulas, or cups (e.g., in case the provided unit dose measuring device is lost or misplaced). In such cases, the kit may be constructed by the end user in accordance with the instructions attached to the bulk container, or with instructions provided by the seller regarding how to appropriately dispense the unit dose or fraction thereof of the product or composition.

[0098] The ketogenic composition may contain, or be administered together with, other supplements known in the art, such as vitamin D3, vitamins, minerals, and nootropics. Examples of vitamin, mineral, and herbal supplements that may be added to the ketogenic composition include one or more of the following: vitamin A, vitamin C, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese, chromium, caffeine, theobromine, theacrine, methylliverine, huperzine A, epicatechin, and enzymes.

[0099] The subject preferably follows a ketogenic diet that restricts carbohydrate and protein intake during the administration period of the composition. In one embodiment, 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 widespread metabolic disorders and provides nutritional support for therapeutic fasting, weight loss, and performance enhancement. Accordingly, the composition is typically administered once, twice, or three times daily to subjects who wish to promote and / or maintain a ketotic state.

[0100] In a preferred embodiment, the ketogenic composition may be administered orally in one or more unit doses per day in powder form, such as a solid and / or powder mixture (e.g., powder-filled gelatin capsules), a strongly pressed tablet, or by other oral administration routes known in the art.

[0101] Oral administration is preferred, but other routes of administration may be used additionally or alternatively. For example, some embodiments may be administered as injections (e.g., subcutaneous, parenteral, or intravenous). The injection may contain one or more other suitable dispersants or wetting / suspending agents, including mannitol, 1,3-butanediol, propylene glycol, water, Ringer's solution, isotonic sodium chloride solution, or synthetic mono or diglycerides and fatty acids containing oleic acid or Cremaphor.

[0102] Exemplary compositions for rectal administration include suppositories that may contain suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters, and polyethylene glycol, which are solid at room temperature but liquefy, soften, and / or dissolve in the rectal lumen at body temperature to release the supplement.

[0103] Exemplary compositions for administration to the nasal cavity or lungs (e.g., aerosol or inhalation provided by heating or spraying) include solutions in physiological saline, which may, for example, contain benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, and / or other solubilizers or dispersants known in the art.

[0104] In some embodiments, the composition is administered in multiple doses over a period of time. The frequency of administration of the composition may vary depending on various factors, such as the timing of the treatment from previous treatments and the purpose of the treatment. The duration of administration of the composition (e.g., the period over which the drug is administered) may vary depending on various factors, such as the subject's response and the desired effect of the treatment.

[0105] The amount of the composition administered may vary depending on factors such as the individual's degree of sensitivity, age, sex, and weight, and the individual's specific constitutional response. “Therapeutic effective dose” is the amount required to promote a therapeutically effective outcome (i.e., therapeutic ketosis) in vivo. According to this disclosure, an appropriate single dose size is the amount that, when administered once or more over an appropriate period, can prevent or alleviate (reduce or eliminate) symptoms in a patient.

[0106] The amount of the composition administered will depend on the efficacy, absorption, distribution, metabolism, and excretion rate of unused ketone bodies, electrolytes, 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 dose will be sufficient to influence the desired response, such as a therapeutic or prophylactic response, to the specific disorder or condition. The compound may be administered as a single dose or in divided doses over time. It should be understood that the administration may be adjusted according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. [Examples]

[0107] IV. Examples Below are example racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, and other ketogenic compositions useful for increasing ketone levels in a subject, and for inducing and 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 also be in the form of salts, esters, dimers, trimers, oligomers, and polymers as described herein. Of importance from the viewpoint of the examples is the enantiomer ratio or proportion of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. The composition may comprise a mixture of R,S-beta-hydroxybutyrate salt and free R,S-beta-hydroxybutyrate to provide a desired electrolyte balance, taste, and / or pharmacokinetic response. In some cases, the composition may comprise a mixture of salts, acids, and esters to provide a desired electrolyte balance and / or regulation of ketosis. Furthermore, the compositions can be combined with short-chain, medium-chain, or long-chain fatty acids, esters, glycers, and other supplements, as disclosed herein, to provide desired levels of elevated ketone bodies and other effects.

[0108] Example 1 A racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition is prepared by combining one or more R-beta-hydroxybutyrate salt compounds, one or more S-beta-hydroxybutyrate salt compounds, R-beta-hydroxybutyrate, and S-beta-hydroxybutyrate, and is provided with 50% enantiomer equivalent of the R-beta-hydroxybutyrate mixed hydrochloride-acid component and 50% enantiomer equivalent of the S-beta-hydroxybutyrate mixed hydrochloride-acid component. The racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition contains less than 100% molar equivalent of racemic R,S-beta-hydroxybutyrate salt and more than 0% molar equivalent of free racemic R,S-beta-hydroxybutyrate.

[0109] Since the racemic mixture contains 50% enantiomer equivalent of the R-beta-hydroxybutyrate mixed hydrochloride-acid compound, the onset of ketosis is accelerated at a given dose compared to the same dose enriched with the S-beta-hydroxybutyrate compound. On the other hand, since the racemic mixture contains 50% enantiomer equivalent of the S-beta-hydroxybutyrate mixed hydrochloride-acid compound, the duration of ketosis is prolonged at a given dose compared to the same dose enriched with the R-beta-hydroxybutyrate compound.

[0110] The racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition can be easily administered as a ketogenic composition, for example, in powder form as a nutritional supplement mixed with food or beverage, in the form of one or more capsules or tablets, or in liquid form such as a mouth spray.

[0111] Example 2 The racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition of Example 1 contains 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%, or 97% by molar equivalent, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97% of racemic acid. Formulated to provide a molar equivalent of 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 racemic R,S-beta-hydroxybutyrate with a miR,S-beta-hydroxybutyrate salt.

[0112] The racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition can be easily administered as a ketogenic composition, for example, in powder form as a nutritional supplement mixed with food or beverage, in the form of one or more capsules or tablets, or in liquid form such as a mouth spray.

[0113] Example 3 Example 1 or Example 2 is modified by combining a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition with a food-safe (i.e., nutritionally) or pharmaceutically acceptable carrier.

[0114] Example 4 Any of the above-described examples can be modified by combining a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition with one or more short-chain fatty acids and / or one or more mono-, di-, or triglycerides thereof (such as triptyline).

[0115] Example 5 Any of the above-described examples can be modified by combining the racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition with one or more medium-chain fatty acids and / or one or more mono-, di-, or triglycerides thereof (such as MCT oil).

[0116] Example 6 Any of the above-described examples can be modified by combining a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition with one or more long-chain fatty acids and / or one or more mono-, di-, or triglycerides thereof.

[0117] Example 7 Any of the above-described examples can be modified by combining the racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition with one or more dietary supplements, such as vitamin D3, vitamins, minerals, and other dietary supplements known in the art.

[0118] Example 8 In any of the above examples, the racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition is used with green tea, green tea extract (for example, a composition containing one or more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), Coleus Modified by combining with one or more fat burner supplements such as forskohlii (i.e., forskolin), yohimbine, rauwarsin, capsaicin, raspberry ketones (e.g., 4-(4-hydroxyphenyl)butan-2-one, p-hydroxybenzylacetone), ephedrine, synephrine (e.g., bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulators and / or adenosine receptor antagonists (e.g., caffeine), nicotine, coca leaf extract, ursolic acid, clenbuterol, norepinephrine reuptake inhibitors (e.g., hordenine, atomoxetine), 7-oxodehydroepiandrosterone (7-ketoDHEA), thyroid hormones (e.g., triiodothyronine), and combinations thereof.

[0119] The resulting combination supplement is expected to provide greater lipolytic and / or fatty acid-reducing effects than similar doses utilizing beta-hydroxybutyrate components enriched with R-beta-hydroxybutyrate or added with S-beta-hydroxybutyrate.

[0120] Example 9 Any of the aforementioned examples involves a racemic R,S-beta-hydroxybutyrate mixed hydrochloride-acid composition containing one or more nootropic supplements such as tyrosine, L-DOPA (L-3,4-dihydroxyphenylalanine), tryptophan, 5-hydroxytryptophan (5-HTP), racetams such as piracetam, oxyracetam, and aniracetam, norepinephrine reuptake inhibitors such as L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, hordenine, and atomoxetine, and plants such as Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia californica, and Convolvulus. Modified by combining pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri, Epimedium herb, Ashwagandha herb, cyclic adenosine monophosphate (cAMP) modulators such as forskolin, stimulants such as nicotine, caffeine, and amphetamine, cholinergic compounds and / or acetylcholine modulators such as huperzine A, dimethylaminoethanol, choline, and alpha-glycerophosphocholine.

[0121] The resulting combination supplement is expected to provide greater cognitive, alertness, and / or mood effects than similar doses utilizing beta-hydroxybutyrate components enriched with R-beta-hydroxybutyrate or added with S-beta-hydroxybutyrate. The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The embodiments described are to be considered illustrative and not limiting in all embodiments. Accordingly, the scope of the present invention is indicated by the appended claims rather than the foregoing description. All modifications that fall within the meaning and scope of equivalents of the claims should be encompassed within their scope.

Claims

1. A racemic R,S-beta-hydroxybutyrate triple-layered composition for increasing ketone levels in a subject, A racemic mixture of beta-hydroxybutyric acid containing 50% R-beta-hydroxybutyric acid by enantiomer equivalent and 50% S-beta-hydroxybutyric acid by enantiomer equivalent, A racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters, and A racemic mixture of beta-hydroxybutyrate salts comprising one or more R-beta-hydroxybutyrate salts in an enantiomer equivalent of 50% and one or more S-beta-hydroxybutyrate salts in an enantiomer equivalent of 50%, Here, the beta-hydroxybutyrate salt is R-beta-hydroxybutyrate sodium, R-beta-hydroxybutyrate potassium, R-beta-hydroxybutyrate calcium, R-beta-hydroxybutyrate magnesium, S-beta-hydroxybutyrate sodium, S-beta-hydroxybutyrate potassium, S-beta-hydroxybutyrate calcium, and, Selected from S-beta-hydroxybutyrate magnesium, The combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 75% to 99.9% of the racemic mixture of beta-hydroxybutyrate salt by molar equivalent and 25% to 0.1% of the racemic mixture of beta-hydroxybutyrate by molar equivalent. The composition is in solid and / or powder form, The racemic R,S-beta-hydroxybutyrate triple-layered composition is formulated to allow administration of higher doses of beta-hydroxybutyrate compounds, limit the occurrence and / or severity of side effects, or both, compared to a racemic R,S-beta-hydroxybutyrate salt composition or a racemic R,S-beta-hydroxybutyrate composition.

2. The composition is A racemic mixture of R-beta-hydroxybutyrate sodium and S-beta-hydroxybutyrate sodium. A racemic mixture of R-beta-hydroxybutyrate potassium and S-beta-hydroxybutyrate potassium. A racemic mixture of R-beta-hydroxybutyrate calcium and S-beta-hydroxybutyrate calcium, or It comprises at least two racemic beta-hydroxybutyrate salts selected from the group consisting of a racemic mixture of R-beta-hydroxybutyrate magnesium and S-beta-hydroxybutyrate magnesium, However, at least one of the racemic beta-hydroxybutyrate salts is A racemic mixture of R-beta-hydroxybutyrate calcium and S-beta-hydroxybutyrate calcium, or The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 1, which is a racemic mixture of R-beta-hydroxybutyrate magnesium and S-beta-hydroxybutyrate magnesium.

3. The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 1, wherein the combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 80% to 99.7% of the racemic mixture of beta-hydroxybutyrate salt by molar equivalent and 20% to 0.3% of the racemic mixture of beta-hydroxybutyrate by molar equivalent.

4. The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 1, wherein the combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 85% to 99.5% by molar equivalent of the racemic mixture of beta-hydroxybutyrate salt and 15% to 0.5% by molar equivalent of the racemic mixture of beta-hydroxybutyrate.

5. The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 1, wherein the combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 90% to 99% by molar equivalent of the racemic mixture of beta-hydroxybutyrate salt and 10% to 1% by molar equivalent of the racemic mixture of beta-hydroxybutyrate.

6. A racemic R,S-beta-hydroxybutyrate triple-layered composition according to any one of claims 1 to 5, further comprising at least one short-chain fatty acid having fewer than six carbon atoms, or a mono-, di-, or triglyceride of the at least one short-chain fatty acid.

7. A racemic R,S-beta-hydroxybutyrate triple-layered composition according to any one of claims 1 to 6, further comprising at least one medium-chain fatty acid having 6 to 12 carbon atoms, or a mono-, di-, or triglyceride of the at least one medium-chain fatty acid.

8. The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 7, comprising at least one medium-chain fatty acid having 8 to 10 carbon atoms.

9. Fat burner supplements to increase lipolysis and / or fatty acid production, or A racemic R,S-beta-hydroxybutyrate triple-layered composition according to any one of claims 1 to 8, further comprising at least one of a nootropic supplement for enhancing cognitive ability, attention, and / or mood.

10. The aforementioned fat burner supplement contains green tea, green tea extract, isolated green tea catechins, epigallocatechin gallate (EGCG), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), and Coleus A racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 9, selected from the group consisting of forskohli, yohimbine, rauwarsin, capsaicin, raspberry ketone, 4-(4-hydroxyphenyl)butan-2-one, p-hydroxybenzylacetone, ephedrine, synephrine, octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulator and / or adenosine receptor antagonist, caffeine, nicotine, coca leaf extract, ursolic acid, clenbuterol, norepinephrine reuptake inhibitor, hordenine, atomoxetine, 7-oxodehydroepiandrosterone, triiodothyronine, and combinations thereof.

11. The aforementioned nootropic supplements include tyrosine, L-DOPA, tryptophan, 5-hydroxytryptophan, racetam, piracetam, oxyracetam, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitor, hordenine, atomoxetine, ginseng (Panax ginseng), ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, California poppy (Eschscholzia californica), and Convolvulus. A racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 9 or 10, selected from the group consisting of pluralis, Centella asiatica, Evoluvulus alsinoides, Bacopa monnieri, Epimedium herb, Ashwagandha herb, cyclic adenosine monophosphate (cAMP) modulator, forskolin, nicotine, caffeine, amphetamine, coca leaf extract, cholinergic compounds, acetylcholine modulator, huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine, and combinations thereof.

12. A racemic R,S-beta-hydroxybutyrate triple-layered composition for increasing ketone levels in a subject, A racemic mixture of beta-hydroxybutyric acid containing 50% R-beta-hydroxybutyric acid by enantiomer equivalent and 50% S-beta-hydroxybutyric acid by enantiomer equivalent, A racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters, and A racemic mixture of beta-hydroxybutyrate salts comprising one or more R-beta-hydroxybutyrate salts in an enantiomer equivalent of 50% and one or more S-beta-hydroxybutyrate salts in an enantiomer equivalent of 50%, Here, the beta-hydroxybutyrate salt is R-beta-hydroxybutyrate sodium, R-beta-hydroxybutyrate potassium, R-beta-hydroxybutyrate calcium, R-beta-hydroxybutyrate magnesium, S-beta-hydroxybutyrate sodium, S-beta-hydroxybutyrate potassium, S-beta-hydroxybutyrate calcium, and Selected from S-beta-hydroxybutyrate magnesium, However, at least one of the beta-hydroxybutyrate salts is a calcium salt or a magnesium salt. The combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 75% to 99.9% of the racemic mixture of beta-hydroxybutyrate salt by molar equivalent and 25% to 0.1% of the racemic mixture of beta-hydroxybutyrate by molar equivalent. The composition provides a combination of 0.5 g to 25 g of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, and is provided as 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, lollipops, lozenges, nutritional supplements, flavored mouth sprays, or suppositories, or is provided contained within them. The racemic R,S-beta-hydroxybutyrate triple-layered composition is formulated to allow administration of higher doses of beta-hydroxybutyrate compounds, limit the occurrence and / or severity of side effects, or both, compared to a racemic R,S-beta-hydroxybutyrate salt composition or a racemic R,S-beta-hydroxybutyrate composition.

13. The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 12, wherein the combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 80% to 99.8% of the racemic mixture of beta-hydroxybutyrate salt and 20% to 0.2% of the racemic mixture of beta-hydroxybutyrate by molar equivalent.

14. A racemic R,S-beta-hydroxybutyrate triple-layered composition for increasing ketone levels in a subject, Food- or pharmaceutically acceptable carriers selected from the group consisting of 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, lollipops, lozenges, dietary supplements, flavored mouth sprays, and suppositories. A racemic mixture of beta-hydroxybutyric acid containing 50% R-beta-hydroxybutyric acid by enantiomer equivalent and 50% S-beta-hydroxybutyric acid by enantiomer equivalent, A racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters, and A racemic mixture of beta-hydroxybutyrate salts comprising one or more R-beta-hydroxybutyrate salts in an enantiomer equivalent of 50% and one or more S-beta-hydroxybutyrate salts in an enantiomer equivalent of 50%, The aforementioned beta-hydroxybutyrate salt is R-beta-hydroxybutyrate sodium, R-beta-hydroxybutyrate potassium, R-beta-hydroxybutyrate calcium, R-beta-hydroxybutyrate magnesium, S-beta-hydroxybutyrate sodium, S-beta-hydroxybutyrate potassium, S-beta-hydroxybutyrate calcium, and Selected from S-beta-hydroxybutyrate magnesium, However, at least one of the beta-hydroxybutyrate salts is a calcium salt or a magnesium salt. Here, the combination of the racemic mixture of beta-hydroxybutyrate and the racemic mixture of beta-hydroxybutyrate salt comprises 75% to 99.9% of the racemic mixture of beta-hydroxybutyrate salt by molar equivalent and 25% to 0.1% of the racemic mixture of beta-hydroxybutyrate by molar equivalent. The aforementioned composition provides a combination of 0.5 g to 25 g of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, The racemic R,S-beta-hydroxybutyrate triple-layered composition is formulated to allow administration of higher doses of beta-hydroxybutyrate compounds, limit the occurrence and / or severity of side effects, or both, compared to a racemic R,S-beta-hydroxybutyrate salt composition or a racemic R,S-beta-hydroxybutyrate composition.

15. The racemic R,S-beta-hydroxybutyrate triple-layered composition according to claim 14, wherein the composition comprises a racemic mixture of 80% to 99.7% by molar equivalent of a beta-hydroxybutyrate salt and a racemic mixture of 20% to 0.3% by molar equivalent of beta-hydroxybutyric acid.

16. A kit for administering ketone bodies to a subject, A racemic R,S-beta-hydroxybutyrate triple-layered composition according to any one of claims 1 to 15, The container in which the composition is placed, and A kit comprising a measuring device configured to hold a unit dose or fraction of the composition, wherein the unit dose of the composition contains 0.5 g to 25 g of a beta-hydroxybutyrate compound.

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

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

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