JP2024014874A - Racemic beta-hydroxybutyrate mixed salt-acid compositions and kits - Google Patents

Abstract

The present invention provides racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions and kits for increasing ketone body levels in a subject. The ketogenic composition includes a racemic mixture of R- and S-beta-hydroxybutyrate and a racemic mixture of R- and S-beta-hydroxybutyrate salts. The composition includes the R-enantiomer to raise ketone bodies and increase the rate at which ketosis is achieved, and the same amount of the S-enantiomer to provide an alternative benefit. R- and S-beta-hydroxybutyric acid is absorbed and utilized by the body more quickly than salts or esters, improving taste and reducing the need to include citric acid or other food acids. R- and S-beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and can provide one or more electrolytes. [Selection diagram] None

Description

Described herein are racemic beta-hydroxybutyrate compounds, particularly salts and acids of racemic beta-hydroxybutyrate, and racemic beta-hydroxybutyrate mixed salt-acid compound compositions for producing elevated blood levels of ketone bodies in a subject. The use of the object is disclosed.

During periods of fasting, strenuous exercise, and/or low carbohydrate consumption, the body's glucose and glycogen stores can be rapidly depleted and rapidly depleted. Failure to replenish glucose stores due to their depletion causes the body to metabolically shift to producing and using ketone bodies for energy ("ketosis"). Ketone bodies can be used by the body's cells as fuel to meet the body's energy needs, including those of the brain and heart. For example, during long-term fasting, blood ketone levels can increase by 2-3 mmol/L or more. When blood ketones rise above 0.5 mmol/L, the heart, brain, and peripheral tissues are using ketone bodies (e.g., beta-hydroxybutyrate, and acetoacetate) as their primary fuel source. Traditionally understood. This state is called ketosis. A state in which blood levels are between 1.0 mmol/L and 3.0 mmol/L is called "nutritional ketosis."

Upon entering ketosis, in other words, during ketogenic metabolism in the liver, the body uses dietary fat and body fat as its primary energy source. As a result, once in ketosis, the body can induce fat loss by controlling dietary fat intake and maintaining low carbohydrate intake and blood levels to maintain ketosis.

During ketosis, the body enters a ketogenic state and essentially burns fat as its primary fuel source. In the body, fats are broken down into fatty acids and glycerol, and the fatty acids are converted into acetyl-CoA molecules, which, through ketogenesis, are converted into the water-soluble ketone body beta-hydroxybutyrate (or “β-hydroxybutyrate”) in the liver. acetoacetate (also known as acetylacetonate), and acetone. Beta-hydroxybutyrate and acetoacetate are the main ketone bodies used for energy in the body, with acetone being removed and excreted as a byproduct of ketogenesis.

The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, promotion of brain metabolism, neuroprotection, muscle-sparing properties, and improved cognitive and physical performance. Science-based improvements in the efficiency of cellular metabolism, managed by ketone supplementation, have beneficial effects on physical, cognitive, and psychological health, and are associated with obesity, cardiovascular disease, neurodegenerative diseases, diabetes, and potentially long-term health effects on common avoidable diseases such as cancer.

Although pursuing a ketogenic diet and lifestyle and maintaining a state of nutritional ketosis has numerous health benefits, significant barriers to pursuing and maintaining a ketogenic state remain. One of the barriers is the difficulty of transitioning to a ketogenic state. The fastest endogenous way to enter ketosis is through depletion of the body's glucose stores through fasting combined with exercise. This is physically and mentally demanding and extremely difficult for even the most motivated and disciplined person.

Additionally, the transition to ketosis is often accompanied by hypoglycemia, which can cause lethargy and lightheadedness in many cases, resulting in an unpleasant physical and mental illness commonly referred to as the "low-carbohydrate cold." You may fall into a state of Many people also experience downregulation in their metabolism as the body naturally goes into "energy saving" mode. Some believe that these temporary symptoms can last for as long as two to three weeks. During this transition period, if the subject consumes a meal or snack containing more than the restricted amount of carbohydrates, ketogenesis immediately ceases and the body leaves the state of ketosis. The body then returns to using glucose as its primary fuel, and the transition to ketosis must begin all over again.

If a subject succeeds in establishing ketosis, maintaining it can be just as difficult, if not more difficult, as the diet must strictly maintain a ratio of carbohydrates and protein to fat. . It is further complicated by the disruption of normal electrolyte balance that often occurs when entering and maintaining a ketogenic state. Depletion and reduction of glycogen stores in the liver and muscles reduces the body's ability to retain water and increases the frequency of urination, which causes greater loss of electrolytes. Lowering insulin levels due to ketosis can also affect the rate at which certain electrolytes are excreted by the kidneys, further reducing electrolyte levels in the body. Negative effects of electrolyte imbalance include muscle pain, spasms, twitching and weakness, restlessness, anxiety, frequent headaches, extreme thirst, insomnia, fever, heart palpitations or arrhythmia, and gastrointestinal symptoms (rapid (such as 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 of the joints, and dizziness (especially (including when standing up suddenly).

Some compositions used to promote ketosis in mammals include those by Lowery et al., disclosed in U.S. Patent Application Publication No. 2017/0296501, which contain the endogenous form of beta-hydroxybutyrate. , i.e., R-beta-hydroxybutyrate, whereas Lowery et al. recommended the use of non-endogenous enantiomers or S-beta-hydroxybutyrate, as well as racemic mixtures of R- and S-beta-hydroxybutyrate. Not yet. Other compositions, such as those disclosed in Clarke et al., US Pat. No. 8,642,654, contain mostly or entirely a single beta-hydroxybutyrate ester (3R)-hydroxybutyl - Consists of hydroxybutyrate. The exclusion of enantiomers that are not endogenous forms of beta-hydroxybutyrate is based on the belief that S-beta-hydroxybutyrate (also known as (3S)-hydroxybutyrate) is ineffective or harmful. ing.

US Patent Application Publication No. 2017/0296501 U.S. Patent No. 8,642,654

(overview)
Herein, racemic R,S-beta-hydroxybutyrate mixed salt-acid in increasing ketone body levels in a subject, including promoting and/or sustaining ketosis in a subject over an extended period of time. Compositions and methods of use are disclosed.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions disclosed herein are racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate salts (“R, and a racemic mixture of R-beta-hydroxybutyric acid and S-beta-hydroxybutyrate (“R,S-beta-hydroxybutyrate”). A "racemic mixture" of R,S-beta-hydroxybutyrate salts comprises enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyrate salts. A "racemic mixture" of R,S-hydroxybutyric acid includes enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyric acid.

R-beta-hydroxybutyrate is the endogenous form produced by mammals, and S-beta-hydroxybutyrate can be supplemented exogenously by administration of a racemic RS-beta-hydroxybutyrate mixed salt-acid composition. enters the body through Thus, although the racemic RS-beta-hydroxybutyrate mixed salt-acid composition contains separate components that have different functions in the body, it differs from administration of the R-beta-hydroxybutyrate compound alone. In comparison, enhanced ketogenic effects are obtained, including more sustained blood ketone levels. The R,S-beta-hydroxybutyrate mixed salt-acid composition provides at least a "double racemic stack" of beta-hydroxybutyrate compounds.

The R-beta-hydroxybutyrate enantiomer is produced endogenously by mammals during ketosis, and therefore the exogenously administered R-beta-hydroxybutyrate mixed salt-acid component is useful for energy production (e.g., glucose). provides additional amounts and/or increased blood plasma levels of R-beta-hydroxybutyrate that can be readily utilized by the body, such as as an alternative energy source). The S-beta-hydroxybutyrate component, which is not produced endogenously by mammals, complements the R-beta-hydroxybutyrate component and produces one or more desired effects not produced by the R-beta-hydroxybutyrate component. bring to mammals.

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

Exogenous delivery of racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions results in relatively more sustained blood ketone body levels primarily due to the S-beta-hydroxybutyrate mixed salt-acid component. In addition, a relatively rapid increase in blood ketone body levels can be beneficially provided primarily by the R-beta-hydroxybutyrate mixed salt-acid component, especially R-beta-hydroxybutyric acid. Such racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions can effectively and relatively quickly induce ketosis in a subject, while at the same time providing S-beta-hydroxybutyrate mixed salt-acid compositions. The regulating effects of the acid component allow ketone bodies to enter the bloodstream in a sustained and long-term manner, providing the ketogenic effects that the body needs.

Combining R,S-beta-hydroxybutyric acid with one or more R,S-beta-hydroxybutyrate salts reduces electrolyte loading, increases absorption, improves taste, facilitates formulation, It is highly beneficial as it reduces the need to add citric acid or other food acids to obtain compositions with neutral or acidic pH.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions described herein are combined with one or more other dietary and/or It may also be combined (eg, in direct admixture or co-administered) with pharmaceutically acceptable supplements/drugs. The unique properties of racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions are that they are composed of either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate, and/or The combination supplement can be beneficially enhanced when compared to other similar combination supplements using enriched beta-hydroxybutyrate compositions. For example, compositions intended to enhance lipolysis and/or fatty acid oxidation (referred to herein as "fat burner" ingredients) may be combined with synergistic lipolytic and/or fat burning effects. It can be combined with a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition to form a supplement. In another example, compositions intended to enhance mental alertness, cognition, and/or mood (referred to herein as "nootropic" ingredients) may have synergistic cognitive, alertness, and/or mood effects. or can be combined with a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition to form a combination supplement with mood effects.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions disclosed herein are administered in a nutritionally or pharmaceutically effective amount as disclosed herein. Used in a method of increasing ketone body levels in a subject (including promoting and/or maintaining ketosis in a subject) comprising administering one or more compositions to a subject in need thereof. Good too. Examples of the beneficial effects of increased ketone body levels in a subject include appetite suppression, weight loss, fat loss, lower blood glucose levels, improved mental alertness, anxiolytic effects (anti-anxiety), Reduce response time, increase physical energy, improve cognitive function, reduce traumatic brain injury, reduce the effects of diabetes, improve neuropathy, reduce cancer, reduce inflammation, anti-aging, anti-glycation, epilepsy Includes one or more of reducing seizures, improving mood, increasing physical strength, increasing muscle mass, or improving body composition.

The composition may include a nutritionally or pharmaceutically acceptable carrier.

Embodiments include a "racemic stack" of at least four different beta-hydroxybutyrate compounds. R-beta-hydroxybutyrate and S-beta-hydroxybutyrate include the free acids (i.e., R-beta-hydroxybutyric acid and S-beta-hydroxybutyrate), their salts (i.e., R-beta-hydroxybutyrate salts). and S-beta-hydroxybutyrate salts), and optionally esters thereof (ie, R-beta-hydroxybutyrate esters and S-beta-hydroxybutyrate esters). It is advantageous to provide the beta-hydroxybutyrate as a double racemic stack combining at least four separate forms of beta-hydroxybutyrate (or a triple racemic stack combining six separate forms). In particular, it may be possible to use higher amounts of beta-hydroxybutyrate for a given dose and/or to allow higher doses per day. Each form of beta-hydroxybutyrate is typically associated with its own particular positive properties and negative side effects. Stacking different forms of beta-hydroxybutyrate can provide more positive properties than each used alone. Similarly, stacking different forms of beta-hydroxybutyrate reduces or alleviates the negative side effects of each particular form of beta-hydroxybutyrate and "disperses" such negative effects. can be restricted. In either case, stacking increases or maximizes the overall dose of beta-hydroxybutyrate that can be effectively delivered.

That is, the present invention provides the following.

The present invention is a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject, comprising:
a racemic mixture of beta-hydroxybutyric acid comprising 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric acid;
Racemic mixture of beta-hydroxybutyrate salts comprising 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts wherein the beta-hydroxybutyrate salt is
Sodium R-beta-hydroxybutyrate,
Potassium R-beta-hydroxybutyrate,
R-beta-hydroxybutyrate calcium,
R-beta-hydroxybutyrate magnesium,
Sodium S-beta-hydroxybutyrate,
Potassium S-beta-hydroxybutyrate,
Calcium S-beta-hydroxybutyrate, and
a racemic mixture selected from magnesium S-beta-hydroxybutyrate;
providing a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition, said composition being in solid and/or powder form;
Preferably, the composition comprises:
racemic mixture of sodium R,S-beta-hydroxybutyrate,
Racemic mixture of potassium R,S-beta-hydroxybutyrate,
at least two of: a racemic mixture of calcium R,S-beta-hydroxybutyrate; or a racemic mixture of magnesium R,S-beta-hydroxybutyrate;
Preferably, the composition comprises 75% to 99.9% by molar equivalents of a racemic mixture of beta-hydroxybutyrate salts and 25% to 0.1% by molar equivalents of a racemic mixture of beta-hydroxybutyric acid. ,
Preferably, the composition comprises 80% to 99.7% by molar equivalents of a racemic mixture of beta-hydroxybutyrate salts and 20% to 0.3% by molar equivalents of a racemic mixture of beta-hydroxybutyric acid. ,
Preferably, the composition comprises 85% to 99.5% by molar equivalents of a racemic mixture of beta-hydroxybutyrate salts and 15% to 0.5% by molar equivalents of a racemic mixture of beta-hydroxybutyric acid. ,
Preferably, the composition comprises 90% to 99% by molar equivalents of a racemic mixture of beta-hydroxybutyrate salts and 10% to 1% by molar equivalents of a racemic mixture of beta-hydroxybutyric acid.
Preferably, it further comprises at least one short chain fatty acid having less than 6 carbons, or a mono-, di- or triglyceride of said at least one short chain fatty acid.
Preferably, it further comprises at least one medium chain fatty acid having 6 to 12 carbons, such as 8 to 10 carbons, or a mono-, di- or triglyceride of said at least one medium-chain fatty acid.
Preferably, a fat burner supplement to increase lipolysis and/or fatty acid oxidation, or
further comprising at least one of a nootropic supplement for enhancing cognitive performance, alertness, and/or mood;
Preferably, one or more of said fat burner supplements include green tea, green tea extract, isolated green tea catechins, epigallocatechin gallate (EGCG), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA). ), Coleus forskohlii, yohimbine, rauwolsucin, 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, noradrenaline reuptake inhibitor, hordenine, atomoxetine, 7-oxodehydroepiandrosterone, triiodothyro selected from the group consisting of nin, and combinations thereof;
Preferably, at least one nootropic compound is tyrosine, L-DOPA, tryptophan, 5-hydroxytryptophan, racetam, piracetam, oxiracetam, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine. , norepinephrine reuptake inhibitor, hordenine, atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira pua ma), Eschscholzia californica, Convolvulus pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa moniari, Epimedium herb, Ashwagandha herb ), cyclic adenosine monophosphate (cAMP) modulator, forskolin, nicotine, caffeine , amphetamine, coca leaf extract, cholinergic compounds, acetylcholine modulators, huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine, and combinations thereof.
Preferably, it further comprises a racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters.

The present invention is a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject, comprising:
A racemic mixture of beta-hydroxybutyric acid comprising 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric acid, and 50% by enantiomeric equivalents of one or more R- A racemic mixture of beta-hydroxybutyrate salts comprising a beta-hydroxybutyrate salt and 50% by enantiomeric equivalent of one or more S-beta-hydroxybutyrate salts, wherein said beta-hydroxybutyrate salt is ,
Sodium R-beta-hydroxybutyrate,
Potassium R-beta-hydroxybutyrate,
R-beta-hydroxybutyrate calcium,
R-beta-hydroxybutyrate magnesium,
Sodium S-beta-hydroxybutyrate,
Potassium S-beta-hydroxybutyrate,
Calcium S-beta-hydroxybutyrate, and
a racemic mixture selected from magnesium S-beta-hydroxybutyrate;
The composition may be a tablet, capsule, powder, food, food additive, flavored beverage, vitamin-fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin-fortified beverage additive, non-alcoholic beverage additive, candy, bar. racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions, which are provided as or in a candies, troches, dietary supplements, flavored mouth sprays, or suppositories;
Preferably, the composition comprises 75% to 99.9% by molar equivalents of a racemic mixture of beta-hydroxybutyrate salts and 25% to 0.1% by molar equivalents of a racemic mixture of beta-hydroxybutyric acid. .

The present invention is a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject, comprising:
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, troches, a dietary or pharmaceutically acceptable carrier selected from the group consisting of dietary supplements, flavored mouth sprays, and suppositories;
a racemic mixture of beta-hydroxybutyric acid comprising 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric acid;
Racemic mixture of beta-hydroxybutyrate salts comprising 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts wherein the beta-hydroxybutyrate salt is
Sodium R-beta-hydroxybutyrate,
Potassium R-beta-hydroxybutyrate,
R-beta-hydroxybutyrate calcium,
R-beta-hydroxybutyrate magnesium,
Sodium S-beta-hydroxybutyrate,
Potassium S-beta-hydroxybutyrate,
providing a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition comprising a racemic mixture selected from calcium S-beta-hydroxybutyrate, and magnesium S-beta-hydroxybutyrate;
Preferably, the composition comprises a racemic mixture of beta-hydroxybutyrate salts from 75% to 99.9% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid from 25% to 0.1% by molar equivalents. .

The present invention is a kit for administering ketone bodies to a subject, comprising:
The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of the present invention,
a container in which the composition is placed, and
A measuring device configured to hold therein a unit dose of said composition or a fraction thereof, wherein said unit dose of said composition is from about 0.5 g to about Provided is a kit comprising a measuring device, comprising 25 g;
Preferably, said container is selected from the group consisting of a carton, box, can, jar, bag, pouch, bottle, jug, and keg.
Kit according to claim 17 or 18, wherein the measuring device is preferably selected from the group consisting of a cup, a scoop, a syringe, a dropper, a spatula, a spoon, and a colon irrigation device.

The present invention provides a method of increasing ketone body levels in a subject, comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of a composition of the present invention. ,
Elevated levels of ketone bodies in the subject may be associated with appetite suppression, weight loss, fat loss, lower blood glucose levels, improved mental alertness, anxiolytic effects (anti-anxiety), reduced response time, and increased physical energy. increase, improve cognitive function, reduce traumatic brain injury, reduce the effects of diabetes, improve neuropathy, reduce cancer, reduce inflammation, anti-aging, anti-glycation, reduce epileptic seizures, improve mood, results in one or more of increased physical strength, increased muscle mass, or improved body composition; and
The S-beta-hydroxybutyrate component in the composition is
increased endogenous production of R-beta-hydroxybutyrate and acetoacetate;
endogenous conversion of said S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetoacetate;
endogenous conversion of said S-beta-hydroxybutyrate component to fatty acids and sterols;
prolonging ketosis,
metabolism of said S-beta-hydroxybutyrate component independent of its conversion to R-beta-hydroxybutyrate and/or acetoacetate;
increased fetal growth;
Increased number of years of growth,
decreased endogenous production of acetone during ketosis,
Signal transduction by said S-beta-hydroxybutyrate component that modulates the metabolism of R-beta-hydroxybutyrate and glucose;
antioxidant activity, or
A method is provided for causing at least one of: production of acetyl-CoA.

Additional features and advantages will be described in part in the description that follows, and in part will be obvious from the description, or may be learned by practicing the embodiments disclosed herein. It is to be understood that both the foregoing short summary and the following detailed description are for purposes of illustration and description only and are not intended to limit the scope of the embodiments or claims herein. It is.

FIG. 1A shows that when using "stacked" doses of at least two different forms of racemic R,S-beta-hydroxybutyrate, a single form of racemic R,S-beta-hydroxybutyrate is used. Indicating higher levels of beta-hydroxybutyrate administered compared to butyrate. Figure 1B shows the relative proportions of undesirable side effects expected as a result of treatment with various formulations of beta-hydroxybutyrate, where (1) free R,S-beta-hydroxybutyric acid and ( 2) “dual stack” (i.e., double racemic stack) formulations containing R,S-beta-hydroxybutyrate salts, as well as R,S-beta-hydroxybutyrate esters in addition to the double stack; A “triple stack” (i.e., triple racemic stack) formulation further comprising allows for the administration of larger amounts of beta-hydroxybutyrate compared to when beta-hydroxybutyrate is administered alone; and/or is expected to reduce the occurrence and intensity of side effects. Figure 2 compares the expected release profile of R,S-beta-hydroxybutyrate stack compositions with free acid, salt, and ester single forms and R-beta-hydroxybutyrate stacks. The stacked R,S compositions exhibit an overall extended release profile and a larger area under the curve (AUC). Figure 3 shows the expected relative rates of lipolysis and/or fatty acid oxidation as a result of treatment with a combination weight loss supplement containing a beta-hydroxybutyrate component in combination with other weight loss supplements, and shows the expected relative rates of lipolysis and/or fatty acid oxidation. / or the total amount of fatty acid oxidation (area under the curve) compared to other similar combination supplements/drugs that use beta-hydroxybutyrate components enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate. compared to the combination supplement using racemic R,S-beta-hydroxybutyrate components.

（式中、
Ｘは、水素、金属イオン、アミノ酸からなどのアミノカチオン、アルキル、アルケニル、アリール、またはアシルであってもよい。） (detailed explanation)
1. Definitions The compound “beta-hydroxybutyrate”, also known as β-hydroxybutyrate, 3-hydroxybutyrate, βHB, or BHB, is a hydroxycarboxylic acid with the general formula CH ₃ CH ₂ OHCH ₂ COOH It is the deprotonated form of beta-hydroxybutyric acid. The deprotonated form that exists at typical biological pH levels is CH ₃ CH ₂ OHCH ₂ COO ^- . The general chemical structures shown below represent beta-hydroxybutyrate compounds that may be utilized in the disclosed compositions.

(In the formula,
X may be hydrogen, a metal ion, an amino cation such as from an amino acid, an alkyl, an alkenyl, an aryl, or an acyl. )

When X is hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is a beta-hydroxybutyrate salt. When X is 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.

The term "racemic R,S-beta-hydroxybutyrate" means that enantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate are present in the composition. . The terms "racemic R,S-beta-hydroxybutyrate salt" and "racemic R,S-beta-hydroxybutyrate salt" refer to enantiomerically equivalent amounts (50:50) of total R, - and S-beta-hydroxybutyrate salts are present. The term "racemic R,S-beta-hydroxybutyric acid" means that enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyric acid are present in the composition. The terms "racemic R,S-beta-hydroxybutyrate ester" and "racemic R,S-beta-hydroxybutyrate ester" refer to enantiomerically equivalent amounts (50:50) of total R - and S-beta-hydroxybutyrate esters are present.

The term "R,S-beta-hydroxybutyrate mixed salt-acid composition" refers to enantiomerically equivalent amounts of one or more R-beta-hydroxybutyrate salts and one or more R,S-beta-hydroxybutyrate salts in said composition. S-beta-hydroxybutyrate salt is present, meaning that enantiomerically equivalent amounts (50:50) of free R-beta-hydroxybutyric acid and free S-beta-hydroxybutyric acid are present in said composition. do.

The term "R,S-beta-hydroxybutyrate salt" refers to salts such as crystals, powders, and other solid forms that dissolve in water to form solutions and disperse in liquids to form suspensions or gels. It does not imply or imply any particular physical state. The salt can be prepared by at least partially neutralizing the beta-hydroxybutyric acid with a strong or weak base such as an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate, or a basic amino acid. Can be formed in solution.

The term "free beta-hydroxybutyric acid" refers to the sum of undeprotonated and deprotonated beta-hydroxybutyric acid molecules. Deprotonated beta-hydroxybutyrate molecule generally refers to a molecule (e.g., dissolved in water) that has released a proton to form a hydronium ion (H ₃ O+) and a beta-hydroxybutyrate anion. .

Free beta-hydroxybutyrate molecules are typically not deprotonated to a significant degree when included in a dry powder or other solid form of beta-hydroxybutyrate mixed hydrochloric acid compositions. In such cases, the fractional amount of free beta-hydroxybutyrate in the beta-hydroxybutyrate mixed hydrochloric acid composition on a weight basis is determined by dividing the weight of free beta-hydroxybutyrate by the weight of free beta-hydroxybutyrate and beta-hydroxybutyrate. - divided by the total weight of the hydroxybutyrate salt. On a molar basis, the fractional amount of free beta-hydroxybutyrate in the beta-hydroxybutyrate mixed hydrochloric acid composition is such that the molar equivalents of free beta-hydroxybutyrate are provided by the free beta-hydroxybutyrate and the beta-hydroxybutyrate salt. divided by the sum of the molar equivalents of beta-hydroxybutyrate anions.

When dissolved in water, a portion of beta-hydroxybutyric acid typically dissociates into beta-hydroxybutyrate anions and hydronium ions (H ₃ O+). As a result, the 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 the beta-hydroxybutyrate mixed salt-acid composition, the dissociation of the beta-hydroxybutyrate molecule and the exchange of protons with cations is - It is not understood to change the molar ratio of free beta-hydroxybutyric acid to beta-hydroxybutyrate anion from the hydroxybutyrate salt. The total amount of free beta-hydroxybutyrate molecules in solution is the sum of undeprotonated dissolved beta-hydroxybutyrate molecules and beta-hydroxybutyrate anions formed by deprotonation of beta-hydroxybutyrate molecules. It is.

Stated another way, the total molar equivalents of beta-hydroxybutyric acid in solution, whether deprotonated or not, are (i) the molar equivalents of non-deprotonated beta-hydroxybutyric acid molecules in solution; (ii) the sum of the total molar equivalents of beta-hydroxybutyrate anions (from all sources) and (ii) the total molar equivalents of cationic charge provided by the cations from the beta-hydroxybutyrate salt compound, which is (equal to the total molar equivalents of beta-hydroxybutyrate anions provided by the butyrate salt). 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-hydroxybutyric acid molecules provides one mole of anionic charge and one mole of cationic charge.

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

As an example, a 100 molar equivalent beta-hydroxybutyrate mixed salt-acid composition in dry powder form contains 5% free undeprotonated beta-hydroxybutyric acid and 95% beta-hydroxybutyrate salt on a molar basis. If so, there would be substantially 5 molar equivalents of beta-hydroxybutyric acid molecules and 95 molar equivalents of beta-hydroxybutyrate anions. If there is sufficient water to dissolve the beta-hydroxybutyrate salt and some of the beta-hydroxybutyric acid molecules are deprotonated, the molar equivalents of non-deprotonated beta-hydroxybutyric acid are less than 5. , the molar equivalent of beta-hydroxybutyrate anion will be greater than 95. The degree of deprotonation of beta-hydroxybutyric acid in solution is related to pH.

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

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

As used herein, a "ketogenic composition" refers to a composition that includes inducing and/or sustaining a state of elevated ketone bodies at a desired level, such as ketosis, in a subject to which it is administered. Prescribed to increase body levels.

"Subject" or "patient" as used herein refers to members of the animal kingdom, including, but not limited to, mammals, humans and other primates, rodents, fish, reptiles, and birds. Including. The subject may be any animal in need of, or suspected to be in need of, treatment, treatment, or prophylaxis. Prophylaxis is meant to be done to prevent events that may occur, such as when high glucose or diabetes is present. "Patient" and "subject" are used interchangeably herein.

As used herein, "ketosis" means that blood ketone levels, including both enantiomers of β-hydroxybutyrate, acetoacetate and acetone, are in the range of about 0.5 mmol/L to about 16 mmol/L in a subject. Point to a certain object. Ketosis can improve mitochondrial function, reduce the production of reactive oxygen species, reduce inflammation, and increase the activity of neurotrophic factors. "Keto-adapted" as used herein refers to long-term nutritional ketosis (>1 week) to obtain sustained non-pathological "mild ketosis" or "therapeutic ketosis" .

In some cases, "elevated ketone body levels" may not mean that the subject is in a state of "clinical ketosis," but nevertheless increases energy production and/or ketone body metabolism and signaling. It means an increase in the supply of ketones to exert other beneficial effects on transmission. For example, a "ketone adapted" subject may not necessarily have elevated ketone body serum levels, but rather a more rapid rise in ketone body serum levels compared to a non-ketone adapted subject. The available ketone bodies can be used. In such cases, "elevated ketone body levels" may refer to the total amount and/or proportion of ketone bodies being utilized by the subject, rather than the plasma levels themselves.

As used herein, the term "administration" or "administering" is used to describe the process of delivering the disclosed compositions to a subject. The compositions may be administered in a variety of ways, including orally, intragastrically, and parenterally (including intravenously and intraarterially, as well as other suitable parenteral routes), among others.

The term "combination supplement" is used herein to describe the combination of a beta-hydroxybutyrate component with one or more other supplements and/or drugs. The beta-hydroxybutyrate component and one or more other supplements and/or drugs can be mixed together in the same tablet, capsule, mixed powder, or other dosage form, or separately without direct mixing. The ingredients may be combined directly, such as by placing the ingredients in the same package. However, in other embodiments, the separate components need not be directly combined prior to administration to fall within the scope of this disclosure. For example, the separate components are administered to the subject separately but sufficiently close in time (e.g., within about 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours of each other). , may be considered co-administered and therefore part of a "combination supplement."

II. Racemic R,S-Beta-Hydroxybutyrate Mixed Salt-Acid Composition A composition for increasing ketone body levels in a subject, including promoting and/or sustaining ketosis, comprises: (1) 50% by enantiomeric equivalent; one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of a plurality of S-beta-hydroxybutyrate salts, and (2) 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents. Contains a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition containing 50% S-beta-hydroxybutyrate. The composition may optionally include 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate esters and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate esters. Racemic mixtures of R,S-beta-hydroxybutyrate mixed salt-acid components may provide synergistic effects, such as when used in combination with other components. In such cases, the combined salt and acid form of R,S-beta-hydroxybutyrate has an acceptable pH and taste. R,S-beta-hydroxybutyrate mixed salt-acid compositions provide improved absorption, increased bioavailability, reduced electrolyte loading, and manufacturing advantages compared to racemic R,S-beta-hydroxybutyrate salts and esters. It has substantial advantages such as ease of preparation, greatly improved taste, and reduced need for citric acid or other food acids to obtain compositions with neutral or acidic pH.

In some embodiments, the racemic R,S-beta-hydroxybutyrate mixed salt-acid composition comprises less than 100% racemic R,S-beta-hydroxybutyrate salt and greater than 0% free racemic R , S-beta-hydroxybutyric acid. Racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions have up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4% on a molar basis , 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75 %, 97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97% 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 25%, 20%, 15%, 10%, 8%, 6%, 5%, 4%, or less than 3% total free racemic R,S-beta-hydroxybutyric acid. obtain. The foregoing percentages are expressed on a molar basis (eg, moles of free R,S-beta-hydroxybutyric acid relative to total moles of R,S-beta-hydroxybutyrate compound in both salt and acid forms).

Racemic mixtures of the R-beta-hydroxybutyrate mixed salt-acid component and the S-beta-hydroxybutyrate mixed salt-acid component are the R-beta-hydroxybutyrate enantiomers produced by mammals and the non-naturally occurring or The endogenous form produced by mammals, the R-beta-hydroxybutyrate enantiomer, and the R-beta-hydroxybutyrate enantiomer, an endogenous form produced by mammals, to enhance the ketogenic effect by delivering the undiscovered S-beta-hydroxybutyrate enantiomer, each alone or in enriched form. , an S-beta-hydroxybutyrate enantiomer not naturally produced or found in mammals.

For example, the R-beta-hydroxybutyrate enantiomer is produced endogenously by mammals during ketosis, so administering the R-beta-hydroxybutyrate mixed hydrochloric acid component to a subject can be used to generate energy, etc. , as an energy source to replace glucose), providing additional amounts that are relatively immediately available in the body and/or increasing plasma levels. The presence of the S-beta-hydroxybutyrate mixed salt-acid component provides a more controlled, gradual, and/or this effect can be modulated to provide a prolonged ketogenic effect.

As a further example, racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions may relatively prolong and sustain the increase in blood ketone body levels primarily due to the S-beta-hydroxybutyrate enantiomeric component. In addition, a relatively rapid boost to blood ketone body levels can be advantageously provided primarily through the R-beta-hydroxybutyrate enantiomeric component. Such compositions can effectively and relatively quickly induce ketosis in a subject, while providing sustained and long-term delivery of ketone bodies into the bloodstream, where R-beta - The hydroxybutyrate and S-beta-hydroxybutyrate components together provide synergistic ketogenic benefits to the subject.

In contrast to compositions that intentionally minimize or eliminate S-beta-hydroxybutyrate, racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions are designed to contain one or more desired It contains an equivalent amount of the S-beta-hydroxybutyrate enantiomer that is not endogenously produced by mammals to provide the same effect. For example, by administering the S-beta-hydroxybutyrate mixed salt-acid component together with the R-beta-hydroxybutyrate mixed salt-acid component, (1) (2) endogenous conversion of the S-beta-hydroxybutyrate component to one or both of R-beta-hydroxybutyrate and acetoacetate; (3) fatty acid conversion from the S-beta-hydroxybutyrate component to and endogenous conversion to sterols, (4) prolongation of ketosis, (5) metabolism of the S-beta-hydroxybutyrate component independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate, (6) ) increased fetal growth, (7) increased growth years, (8) decreased endogenous production of acetone during ketosis, (9) S-beta- regulates R-beta-hydroxybutyrate and glucose metabolism. At least one of hydroxybutyrate signaling, (10) antioxidant activity, and (11) acetyl-CoA production may be provided.

Racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions can be used to improve, for example, but not limited to, appetite suppression, weight loss, fat reduction, lowering blood glucose levels, and improving mental alertness. Increase physical energy, improve cognitive function, reduce traumatic brain injury, reduce the effects of diabetes, improve neuropathy, reduce cancer, reduce inflammation, anti-aging, anti-glycation, reduce epileptic seizures, mood may be used to produce one or more desired effects in a subject, including improving body composition, increasing physical strength, increasing muscle mass, or improving body composition.

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

Examples of R,S-beta-hydroxybutyrate salts include salts of alkali metals, alkaline earth metals, transition metals, amino acids, or metabolites of amino acids. 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.

Racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions may optionally include racemic R,S-beta-hydroxybutyrate esters such as mono-, di-, tri-, oligo-, and polyesters. . For example, monoester of ethanol, monoester of 1-propanol, monoester of 1,2-propanediol, diester of 1,2-propanediol, monoester of 1,3-propanediol, monoester of 1,3-propanediol. Diesters, monoesters of S-, R-, or S-R-1,3-butanediol, diesters of S-, R-, or S-R-1,3-butanediol, monoesters of glycerin, (3S )-hydroxybutyl (3S)-hydroxybutyrate monoester, (3R)-hydroxybutyl (3S)-hydroxybutyrate monoester, glycerin diester, glycerin triester, acetoacetate ester, repeating unit of BHB dimers, trimers, oligomers, and polyesters having beta-hydroxybutyrate and one or more of lactic acid, citric acid, acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, and malic acid. with other hydroxycarboxylic acids and/or with beta-hydroxybutyrate and one or more diols such as 1,3-propanediol and 1,3-butanediol, tartaric acid, citric acid, malic acid, succinic acid, and complex oligomers or polymers with one or more polyacids such as fumaric acid and short chain fatty acids such as butyric acid, valeric acid, or caproic acid.

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

Said composition may comprise or be combined with at least one medium chain fatty acid, or a mono-, di- or triglyceride of said at least one medium chain fatty acid, wherein said medium chain fatty acid has between 6 and 12 carbon, preferably 8 to 10 carbons. Examples of medium chain fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, and the like. Medium-chain triglycerides (MCTs), medium-chain fatty acids, and mono- and di-glycerides are ketone bodies that can provide additional sources for the production of ketone bodies independent of R-beta-hydroxybutyrate. It is a precursor.

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

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 purified 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, and salts of medium chain triglycerides. Ester derivatives optionally include alkyl ester derivatives such as methyl, ethyl, propyl, butyl, hexyl, and the like.

Administration of a racemic mixture of the R-beta-hydroxybutyrate mixed salt-acid component and the S-beta-hydroxybutyrate mixed salt-acid component results in a dual effect that provides both: (1) an initial and relatively immediate increase in blood levels of ketone bodies, and (2) a subsequent relatively prolonged rise in blood levels of ketone bodies that (1) rapidly induces ketosis. , (2) The metabolic and physiological advantages of sustained ketosis over time can be utilized.

By increasing blood ketone body levels through exogenous supplementation, compared to methods that aim to induce and maintain ketosis based on diet alone (e.g., fasting and/or carbohydrate restriction), become more flexible in their food choices. For example, a subject administered a racemic mixture of an R-beta-hydroxybutyrate mixed salt-acid component and an S-beta-hydroxybutyrate mixed salt-acid component in appropriate amounts may not be at risk for a ketogenic state. Carbohydrate- or sugar-based foods can now be ingested from time to time without reverting to a glucose-based metabolic state. Additionally, such administration facilitates transition into a state of ketosis and reduces or eliminates the typical deleterious effects associated with transition into a state of ketosis.

In some embodiments, the ketogenic composition further contains a therapeutically effective amount of vitamin _D3 . Vitamin _D3 is believed to work together with magnesium and calcium to promote good bone health and prevent undesirable calcification of soft tissues. In preferred embodiments, the average daily dose of the ketogenic composition comprises, for example, from about ₂₀₀ IU (“International Units”) to about 8000 IU, or from about 400 IU to about 4000 IU, or from about 600 IU to about 3000 IU of vitamin D3. In amounts, vitamin _D3 is contained. In some embodiments, vitamin _D3 is present in an amount such that the average daily dose of the ketogenic composition 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 vitamin D3. ₃ is included.

Some embodiments also include one or more additional ketone precursors or supplements. These additional ketone precursors or supplements may include acetoacetate, ketone esters, and/or other compounds that cause an increase in blood ketone levels without adding more electrolytes into the bloodstream. Acetoacetate can be provided in salt form, ester form, acid form, and combinations thereof. Other additives include metabolites that enhance efficacy or facilitate the transport of ketone bodies into the mitochondria, caffeine, theobromine, and nootropics such as L-alpha glycerylphosphorylcholine (“alpha GPC”).

The composition may include flavoring agents to help mask the sometimes bad taste of the beta-hydroxybutyrate compound (especially when provided in non-salt form). These include essential oils such as peppermint, natural and artificial sweeteners, and other flavorings known in the art.

In some embodiments, the ketogenic composition may further contain one or more additional ingredients configured to reduce the hygroscopicity of the composition. For example, various anti-caking agents, flow agents, and/or hygroscopic agents may be included in types and amounts that are safe for ingestion. Such additional ingredients include aluminosilicates, ferrocyanides, carbonates or bicarbonates, silicates (e.g. sodium or calcium silicate), silica, phosphates (e.g. diphosphate (calcium or tricalcium phosphate), talc, powdered cellulose, calcium carbonate, and the like.

III. Stacking of Racemic R,S-Beta-Hydroxybutyrate Compounds As mentioned above, the racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions described herein are available in three general forms ( It may be provided as: 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 salt and acid forms, and optionally ester forms.

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

The salt form of racemic R,S-beta-hydroxybutyrate is generally considered to be more palatable than the ester form. However, administering clinically or dietaryly effective amounts of racemic R,S-beta-hydroxybutyrate in salt form inherently requires administration of relatively high levels of the corresponding cation. For example, sodium is often used as the cation in beta-hydroxybutyrate salts, and high levels of sodium are known to have negative health effects. Different beta-hydroxybutyrate salts with different cations can be mixed to attenuate the effect of a single cation, yet provide an effective amount of beta-hydroxybutyrate without upsetting the subject/patient's electrolyte balance. It remains difficult to do so.

Accordingly, the free acid form of racemic R,S-beta-hydroxybutyrate (ie, racemic R,S-beta-hydroxybutyric acid) is utilized to form mixed salt-acid compositions. Since beta-hydroxybutyric acid has a pKa of 4.70, it deprotonates to generate H ⁺ at physiological pH. The result is excess acidity, which can cause unwanted side effects such as causing or worsening gastrointestinal problems such as ulcers and reflux.

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 the beta-hydroxybutyrate compound. For example, a beta-hydroxybutyrate stack 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 may provide greater amounts of beta-hydroxybutyrate than a single form before reaching a similar incidence and/or severity of side effects.

This is shown schematically in Figures 1A and 1B. FIG. 1A shows various beta-hydroxybutyrate doses when using a single form (Formulations 1-3), a double stack (Formulations 4-6), and a triple stack (Formulation 7). Although individual tolerance ranges may vary and therefore the illustrated doses are exemplary only, a typical subject may take any dose of beta-hydroxybutyrate to avoid corresponding side effects. One would want to avoid excessive amounts of a single form of. Therefore, stacking different forms of beta-hydroxybutyrate allows for the delivery of more beta-hydroxybutyrate in a given dose compared to the use of a single form, and/or Higher dosing frequency is possible. For example, different forms of beta-hydroxybutyrate can be stacked in a single dose to increase the amount of beta-hydroxybutyrate in that dose and/or different forms of beta-hydroxybutyrate can be stacked in a single dose to increase the amount of beta-hydroxybutyrate in that dose. The rate can be taken in different doses throughout the day to increase the frequency of administration and thus increase the overall daily delivery of beta-hydroxybutyrate.

FIG. 1B shows the expected relative severity of undesirable side effects resulting from treatment with various formulations of beta-hydroxybutyrate, including stacked formulations. A triple stack formulation consisting of each of 1) a salt form of beta-hydroxybutyrate, 2) a free acid form of beta-hydroxybutyrate (i.e., beta-hydroxybutyric acid), and 3) an ester form of beta-hydroxybutyrate. may allow administration of larger amounts of beta-hydroxybutyrate and/or have reduced side effects compared to a double stack consisting of only two such forms of beta-hydroxybutyrate. Be expected. Both triple stacks (i.e., triple racemic stacks) and double stacks (i.e., double racemic stacks) are similarly compared to a single form consisting of only one form of beta-hydroxybutyrate. It is expected that this will allow administration of larger amounts of beta-hydroxybutyrate and/or reduce side effects.

In other words, for a given dose of beta-hydroxybutyrate, the double and triple racemic stacks, compared to the single form, may cause 1) organoleptic side effects, 2) electrolyte imbalance side effects, and/or 3) Can be formulated to have less acidity side effects. For example, a single form of beta-hydroxybutyrate ester may have a threshold dosage that a typical user would not exceed due to negative organoleptic side effects; Butyrate salts may have a threshold dosage limited by recommended dietary restrictions of electrolytes administered with the salt, and beta-hydroxybutyrate in its single form may be less sensitive to the negative effects of acidity than typical users. may have a threshold dose that will not be exceeded for the purpose of treatment. Stacked forms of beta-hydroxybutyrate allow for the supplementation of larger amounts of beta-hydroxybutyrate without exceeding any of the distinct thresholds associated with organoleptic, electrolyte, or acidity side effects. enable.

In some embodiments, the beta-hydroxybutyrate stack comprises (i) one or more R,S-beta-hydroxybutyrate salts, (ii) R,S-beta-hydroxybutyric acid, and ( iii) at least two of one or more beta-hydroxybutyrate esters. For example, the beta-hydroxybutyrate double stack may be about 2% to about 98%, or about 5% to about 95%, or about 10% to about 90%, or about or at least two of components (i), (ii), and (iii) provided from 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60%. good.

Exemplary beta-hydroxybutyrate triple stacks are about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% on a molar basis of beta-hydroxybutyrate. % to about 60% beta-hydroxybutyrate ester, about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, on a molar basis of beta-hydroxybutyrate; from about 20% to about 60% beta-hydroxybutyrate salt, on a molar basis of beta-hydroxybutyric acid from about 2% to about 96%, or from about 5% to about 90%, or from about 10% to about 80%; or about 20% to about 60% beta-hydroxybutyric acid. In some embodiments, the beta-hydroxybutyrate triple stack comprises substantially equal amounts of each of the three forms of beta-hydroxybutyrate on a molar basis of beta-hydroxybutyrate.

Stacked beta-hydroxybutyrate compositions may also provide a more beneficial digestive release profile. Each of the different forms of beta-hydroxybutyrate may interact somewhat differently upon ingestion. For example, the free acid form can be easily delivered to the bloodstream as a usable ketone body, and beta-hydroxybutyrate from the salt form is generally available upon dissolution of the particular salt or salt mixture utilized. Depending on its sexual characteristics, it may take slightly longer to reach the bloodstream, and beta-hydroxybutyrate from the ester form generally takes longer to reach the bloodstream, depending on the rate at which the ester bond undergoes hydrolysis. May take the longest time to reach. Therefore, stacked beta-hydroxybutyrate formulations combine the benefits of faster onset with longer release times, and/or an overall greater pharmacokinetic area under the curve (AUC). can be adjusted to provide a more favorable release profile, such as one that provides a. Stacked compositions can provide timed delivery or availability of ketone bodies, resulting in more uniform blood levels of ketone bodies and a "tail" of delivery of exogenous ketone bodies. ” becomes significantly longer (such as 1 to 8 hours after consuming the stacked composition).

This is illustrated in Figure 2, where the expected release profile of a keto stack composition (e.g., consisting of a free acid and a salt) is compared to each single form of free acid, salt, and ester. There is. Keto stack compositions can provide more overall exogenous ketone bodies and are also provided in multiple different forms with different release characteristics, thereby extending the overall release profile. Provides larger AUC.

FIG. 2 also shows how the release profile can be adjusted by varying the relative amounts of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate. As shown, the beta-hydroxybutyrate in the "R stack" is composed of R-beta-hydroxybutyrate, while the "R/S stack" is composed of R-beta-hydroxybutyrate. It contains a racemic mixture with S-beta-hydroxybutyrate, which flattens and prolongs the release profile.

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

For example, compositions intended to increase lipolysis and/or fat oxidation (referred to herein as "fat burner" ingredients) form a combination supplement with synergistic lipolysis and/or fat burning effects. may be combined with a racemic R,S-beta-hydroxybutyrate component to Without being bound by any particular theory, the fat burner compositions have the following properties: when combined with a racemic R,S-beta-hydroxybutyrate component as compared to when utilized without the beta-hydroxybutyrate component; It is thought that it will be easier to use. That is, the racemic R,S-beta-hydroxybutyrate component may function to effectively "prime" the subject for metabolically efficient utilization of lipids as an energy source. There is. For example, by exogenously supplementing a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition, a subject utilizes such ketone bodies (and thus stored body fat) as an energy source. It is believed to enhance the enzymes and other metabolic mechanisms necessary for Therefore, fat burners may have enhanced pharmacokinetics and/or pharmacodynamics to promote lipolysis and/or fatty acid oxidation at higher levels than when the beta-hydroxybutyrate component or fat burner is administered alone. There is.

These synergistic effects of the combination supplement are due to the fact that the beta-hydroxybutyrate component is not enriched with either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate, but rather with racemic R,S- It is thought that this effect becomes more pronounced when the component is beta-hydroxybutyrate. This is schematically shown in FIG. As shown, for a combination supplement with a given beta-hydroxybutyrate dose, where the beta-hydroxybutyrate component is enriched with R-beta-hydroxybutyrate, the level of fat oxidation/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 fat oxidation/lipolysis is longer lasting than with enriched R-beta-hydroxybutyrate compositions. However, the overall level of fatty acid oxidation/lipolysis remains relatively low overall.

On the other hand, when the beta-hydroxybutyrate component is racemic, the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate components undergo a relatively high initial level of fatty acid oxidation/lipolysis and a relatively long Functions to provide duration of fatty acid oxidation/lipolysis. The racemic R,S-beta-hydroxybutyrate version probably does not provide as high an initial level of fatty acid oxidation/lipolysis as the enriched R-beta-hydroxybutyrate version, and probably does not provide as high an initial level of fatty acid oxidation/lipolysis as the enriched Although it does not provide as long a fatty acid oxidation/lipolysis duration as the S-beta-hydroxybutyrate version, the combined effect of the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate components is enantiomerically equivalent. When provided at a ratio of , an overall higher level of fatty acid oxidation/lipolysis effect is obtained. In other words, when racemic R,S-beta-hydroxybutyrate compositions are utilized in combination supplements, compared to enriched R-beta-hydroxybutyrate or enriched S-beta-hydroxybutyrate, Therefore, the area under the curve is larger.

The fat burner component may include one or more compounds that can promote lipolysis and/or enhanced fat oxidation. For example, the fat burner ingredients may include green tea, green tea extract (e.g., a composition comprising one or more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extract, conjugated linoleic acid. (CLA), tetradecylthioacetic acid (TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4-(4-hydroxyphenyl)butane). -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 (e.g., tea, extracts, isolates, salts, and free bases), ursolic acid, clenbuterol, noradrenaline reuptake inhibitors (e.g., hordenine, atomoxetine), 7-oxodehydro These include epiandrosterone (7-ketoDHEA), thyroid hormones (eg, triiodothyronine), and combinations thereof.

A combination supplement may include a beta-hydroxybutyrate component and a component intended to enhance mental alertness, cognition, and/or mood (referred to herein as a "nootropic" component). Similar to the fat burner embodiment, when the beta-hydroxybutyrate component is a racemic mixture, rather than enriched with R-beta-hydroxybutyrate or S-beta-hydroxybutyrate, a synergistic It is expected that the nootropic effect will be greater.

Exemplary compounds that may be included in the nootropic ingredient include tyrosine, catecholamine precursors such as L-DOPA (L-3,4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP), piracetam, Racetams such as oxiracetam and aniracetam, norepinephrine reuptake inhibitors such as L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, hordenine, and atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvulus pluricaul is, Centella asiatica, Evolvulus alsinoides, Bacopa mannieri, Epimedium herb (Epimedium) herb), Ashwagandha herb, cyclic adenosine monophosphate (cAMP) modulators such as forskolin, stimulants such as nicotine, caffeine, and amphetamines, huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine and/or acetylcholine modulators, and combinations thereof.

Combination supplements utilizing racemic R,S-beta-hydroxybutyrate ingredients may include other supplements/medications in addition to or in place of the fat burner ingredients. For example, combination supplements can suppress appetite, reduce weight, lower blood glucose levels, improve mental alertness, increase physical energy, improve cognitive function, reduce traumatic brain injury, and reduce the effects of diabetes. , improve neurological disorders, reduce cancer, reduce inflammation, prevent aging, anti-glycation, reduce epileptic seizures, improve mood, increase physical strength, increase muscle mass, or improve body composition. It may also contain one or more compounds intended to assist.

In some embodiments, the ketogenic composition includes other vitamin and/or mineral supplements, such as vitamin _D3 , and supplements for glucose control, such as berberine, and other glucose-lowering substances; or may be administered together with them. It is hypothesized that a racemic mixture of R- and S-beta-hydroxybutyrate mixed salt-acid components may provide a more sustained glucose-lowering effect in conjunction with other substances.

V. Administration In some embodiments, the compositions disclosed herein may be used in a method of increasing ketone body levels in a subject, including promoting and/or maintaining ketosis. involves administering a nutritionally or pharmaceutically effective amount of one or more compositions disclosed herein to a subject in need thereof. Examples of the beneficial effects of increasing ketone body levels in a subject, including promoting and/or maintaining ketosis, include appetite suppression, weight loss, fat loss, lower blood glucose levels, and mental alertness. Improves stability, increases physical energy, improves cognitive function, reduces traumatic brain injury, reduces the effects of diabetes, improves neuropathy, reduces cancer, reduces inflammation, anti-aging, anti-glycation, epilepsy This includes one or more of reducing seizures, improving mood, increasing physical strength, increasing muscle mass, or improving body composition.

In some embodiments, R-beta-hydroxybutyrate and Increased endogenous production of acetoacetate, endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate, S-beta-hydroxybutyrate component to fatty acid and endogenous conversion to sterols, prolongation of ketosis, metabolism of the S-beta-hydroxybutyrate component independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate, increased fetal development, growth years of increased, decreased endogenous production of acetone during ketosis, signaling by R-beta-hydroxybutyrate and S-beta-hydroxybutyrate that regulates glucose metabolism, antioxidant activity, and production of acetyl-CoA. One or more of the following are provided.

The ketogenic compositions described herein can be administered to a subject in a therapeutically effective amount and/or at a frequency that induces or maintains ketosis. In some embodiments, a single or unit dose is 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. The total amount of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate components ranges from about 12 grams.

The term "unit dose" refers to a dosage form configured to deliver a specific amount or dose of a composition or its components. Examples of dosage forms include tablets, capsules, powders, foods, food additives, beverages (such as flavored, vitamin-fortified, or non-alcoholic), beverage additives (such as flavored, vitamin-fortified, or non-alcoholic), candy. , suckers, pastilles, dietary supplements, food-acceptable sprays (such as flavored mouth sprays), injectables (such as alcohol-free injections), and suppositories. Not limited to these. Such dosage forms can be constructed to provide a complete unit dose or a fraction thereof (eg, 1/2, 1/3, or 1/4 of a unit dose).

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 colonic irrigation device, and a complete is configured to hold therein a measured amount of the composition equal to a unit dose or a fraction thereof (eg, 1/2, 1/3, or 1/4 of a unit dose). For example, a bulk container such as a carton, box, can, jar, bag, pouch, bottle, jug, or keg containing several unit doses of the composition (e.g., 5-250 or 10-150 unit doses) The user may be provided with a unit dose measuring device configured to provide a unit dose of the product or a component thereof or a fraction thereof.

While the compositions disclosed herein are provided in bulk form, kits used to provide unit doses of the compositions include a bulk container holding an amount of the composition therein; and a unit dose measuring device configured to provide a unit dose or a fraction thereof of the product or a component thereof. One or more unit dose measuring devices may be placed within said bulk container at the time of sale, may be attached to the outside of said bulk container, or may be prepackaged with said bulk container within a larger package. It may be packaged or provided by the vendor or manufacturer for use with one or more bulk containers.

The kit may include instructions regarding the size of the unit dose or fraction thereof and the method and frequency of administration. The instructions may be written on the bulk container, may be pre-packaged together with the bulk container, or may be placed on the packaging material sold together with the bulk container. , may be provided by the vendor or manufacturer (e.g., website, mailer, flyer, product literature, etc.). The instructions may include reference to how to use the unit dose measuring device to suitably provide unit doses or fractions thereof. The instructions may additionally or alternatively include reference to common unit dose measuring devices such as spoons, spatulas, cups, etc. that are not attached to the bulk container (e.g. (in case you lose or misplace your measuring device). In such cases, the kit may be prepared by the end user in accordance with the instructions provided with the bulk container or instructions provided by the vendor on how to properly provide a unit dose of the product, composition, or fraction thereof. can be constructed.

The ketogenic composition may include or be administered with other supplements known in the art, such as vitamin D ₃ , vitamins, minerals, nootropics, and the like. Examples of vitamins, minerals and herbal supplements that may be added to the ketogenic composition include vitamin A, vitamin C, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese. , chromium, caffeine, theobromine, theacrine, methylliverin, huperzine A, epicatechin, and enzymes.

The subject preferably follows a ketogenic diet that limits carbohydrate and protein intake during the period of administration of the composition. In one embodiment, the subject may limit dietary intake to a ratio of about 65% fat, about 25% protein, and about 10% carbohydrate. The resulting therapeutic ketosis provides rapid and sustained keto-adaptation as a metabolic therapy for a wide range of metabolic disorders, and provides nutritional support for therapeutic fasting, weight loss, and performance enhancement. In light of this, the compositions are typically administered once a day, twice a day, or three times a day to a subject desiring to promote and/or maintain a state of ketosis.

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

Although oral administration is preferred, other routes of administration may additionally or alternatively be utilized. For example, some embodiments may be administered as an injection (eg, subcutaneously, parenterally, or intravenously). Injectables may be prepared using mannitol, 1,3-butanediol, propylene glycol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants containing synthetic mono- or diglycerides and fatty acids, including oleic acid or Cremaphor. Alternatively, it may contain one or more wetting and suspending agents.

Exemplary compositions for rectal administration include suppositories, which may contain suitable non-irritating excipients, such as, for example, cocoa butter, synthetic glyceride esters, polyethylene glycols, etc., which are solid at room temperature but at body temperature. In the rectal cavity, the supplement is liquefied, softened, and/or dissolved to release the supplement.

Exemplary compositions for nasal or pulmonary administration (e.g., aerosol or inhalation provided by heating or nebulization) include, e.g., benzyl alcohol or other suitable preservative, absorption to enhance bioavailability. Solutions in saline are included, which may include accelerators and/or other solubilizing or dispersing agents known in the art.

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 any of a variety of factors, such as timing of treatment from previous treatment, purpose of treatment, etc. The period of administration of the composition (eg, the period during which the drug is administered) can vary depending on any of a variety of factors, including the response of the subject, the desired effect of the treatment, and the like.

The amount of the composition administered may vary depending on factors such as the individual's degree of susceptibility, the individual's age, sex, and weight, the individual's idiosyncratic response. A "therapeutically effective amount" is the amount necessary to promote a therapeutically effective result (ie, therapeutic ketosis) in vivo. In accordance with the present disclosure, a suitable single dose size is an amount that can prevent or alleviate (reduce or eliminate) symptoms in a patient when administered one or more times over a suitable period of time.

The amount of composition administered will depend on the potency, absorption, distribution, metabolism, and excretion rate of unused ketone bodies, electrolytes, method of administration, the particular disorder being treated, and other factors known to those skilled in the art. It is decided. Taking into account the severity of the condition to be alleviated, the dose shall be sufficient to affect the desired response, such as a therapeutic or prophylactic response to the particular disorder or condition. The compound may be administered once or in divided doses over time. It is to be understood that the administration may be adjusted according to the individual needs and professional judgment of the person administering or supervising the administration of the composition.

IV. EXAMPLES Described below are exemplary racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and other ketogenic compositions useful for increasing ketone levels in a subject. , including inducing and maintaining a ketogenic state in subjects to whom they are administered. It should be appreciated that the beta-hydroxybutyrate compounds described in the Examples may be in the form of salts, esters, dimers, trimers, oligomers and polymers as described herein. What is important from the point of view of the examples is the enantiomeric proportion or ratio of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. The composition comprises a mixture of R,S-beta-hydroxybutyrate salt and free R,S-beta-hydroxybutyrate to provide the desired electrolyte balance, taste, and/or pharmacokinetic response. obtain. In some cases, the composition may be a mixture of salts, acids, and esters to provide the desired electrolyte balance and/or ketosis regulation. The compositions can also be combined with short, medium, or long chain fatty acids, esters, glycerides, and other supplements to achieve desired elevated levels of ketone bodies, as disclosed herein. and other effects.

Example 1
By combining one or more R-beta-hydroxybutyrate salt compounds, one or more S-beta-hydroxybutyrate salt compounds, R-beta-hydroxybutyric acid, and S-beta-hydroxybutyrate, racemic R, An S-beta-hydroxybutyrate mixed salt-acid composition is prepared, comprising a mixture of 50% R-beta-hydroxybutyrate mixed salt-acid component by enantiomeric equivalent and 50% S-beta-hydroxybutyrate by enantiomeric equivalent. Provided as a salt-acid component. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition comprises less than 100% by molar equivalents of racemic R,S-beta-hydroxybutyrate salt and more than 0% by molar equivalents of free racemic R, Contains S-beta-hydroxybutyric acid.

Since the racemic mixture contains 50%, by enantiomeric equivalents, of the R-beta-hydroxybutyrate mixed salt-acid compound, at a given dose it can be compared with the same dose enriched with the S-beta-hydroxybutyrate compound. In comparison, ketosis occurs faster. On the other hand, since the racemic mixture contains 50%, by enantiomeric equivalent, of the S-beta-hydroxybutyrate mixed salt-acid compound, at a given dose, the same dose enriched with the R-beta-hydroxybutyrate compound Compared to the amount, ketosis lasts longer.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition can be prepared, for example, in powder form as a dietary supplement mixed with food or drink, in the form of one or more capsules or tablets, or in liquid form such as a mouth spray. It is easily administered as a ketogenic composition.

Example 2
The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of Example 1 has a molar equivalent of 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% and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97% 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% free racemic R,S-beta-hydroxybutyric acid. prescribed to do so.

The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition can be prepared, for example, in powder form as a dietary supplement mixed with food or drink, in the form of one or more capsules or tablets, or in liquid form such as a mouth spray. It is easily administered as a ketogenic composition.

Example 3
Example 1 or Example 2 provides that by combining a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition with a dietary (i.e., nutritionally) or pharmaceutically acceptable carrier, be modified.

Example 4
Any of the foregoing embodiments may include racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions containing one or more short chain fatty acids, and/or one or more mono-, di-, or Modified by combination with triglycerides (such as tributyrin).

Example 5
Any of the foregoing embodiments may include racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions containing one or more medium chain fatty acids, and/or one or more mono-, di-, or Modified by combination with triglycerides (such as MCT oil).

Example 6
Any of the foregoing embodiments may include racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions containing one or more long chain fatty acids, and/or one or more mono-, di-, or Modified by combination with triglycerides.

Example 7
Any of the foregoing embodiments may include combining the racemic R,S-beta-hydroxybutyrate mixed salt-acid composition with one of the following nutritional supplements, such as vitamin D ₃ , vitamins, minerals, and other dietary supplements known in the art. Modified by combining with the above nutritional supplements.

Example 8
Any of the foregoing embodiments may further comprise injecting the racemic R,S-beta-hydroxybutyrate mixed salt-acid composition into one or more isolated forms of green tea, green tea extract, such as epigallocatechin gallate (EGCG). a composition comprising green tea catechins), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwalsin, capsaicin, raspberry ketones (e.g. -(4-hydroxyphenyl)butan-2-one, p-hydroxybenzylacetone), ephedrine, synephrine (e.g. bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulator and / or adenosine receptor antagonists (e.g. caffeine), nicotine, coca leaf extract, ursolic acid, clenbuterol, noradrenaline reuptake inhibitors (e.g. hordenine, atomoxetine), 7-oxodehydroepiandrosterone (7-keto DHEA) ), thyroid hormone (e.g., triiodothyronine), and combinations thereof.

The resulting combination supplement provides greater lipolysis than similar doses utilizing beta-hydroxybutyrate components enriched with R-beta-hydroxybutyrate or added with S-beta-hydroxybutyrate. and/or are expected to provide fatty acid oxidation effects.

Example 9
Any of the foregoing examples may include racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions containing one or more of tyrosine, L-DOPA (L-3,4-dihydroxyphenylalanine), tryptophan, Nootropic supplements such as 5-hydroxytryptophan (5-HTP), racetams such as piracetam, oxiracetam, and aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, hordenine, and atomoxetine. Norepinephrine reuptake inhibitor, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Polygala Eschscholzia californica), Convolvulus pluricaulis, Centella asiatica , Evolvulus alsinoides, Bacopa moniari, Epimedium herb, Ashwagandha herb, forskolin and other cyclic adenosine monophosphate (cAMP) modules. such as nicotine, caffeine, and amphetamines. stimulants, cholinergic compounds and/or acetylcholine modulators, such as huperzine A, dimethylaminoethanol, choline, and alpha-glycerophosphocholine, and combinations thereof.

The resulting combination supplement provides greater cognitive benefit than similar doses utilizing beta-hydroxybutyrate components enriched with R-beta-hydroxybutyrate or added with S-beta-hydroxybutyrate. , is expected to provide arousal, and/or mood effects. The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are in all respects to be considered illustrative only and not limiting. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims (19)

A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject, the composition comprising:
a racemic mixture of beta-hydroxybutyric acid comprising 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric acid;
Racemic mixture of beta-hydroxybutyrate salts comprising 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts including;
wherein the composition comprises a racemic mixture of beta-hydroxybutyrate salts from 75% to 99.9% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid from 25% to 0.1% by molar equivalents. ,
The beta-hydroxybutyrate salt is
Sodium R-beta-hydroxybutyrate,
Potassium R-beta-hydroxybutyrate,
R-beta-hydroxybutyrate calcium,
R-beta-hydroxybutyrate magnesium,
Sodium S-beta-hydroxybutyrate,
Potassium S-beta-hydroxybutyrate,
Calcium S-beta-hydroxybutyrate, and
S-beta-hydroxybutyrate magnesium;
Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition, wherein said composition is in solid and/or powder form. The composition is
racemic mixture of sodium R-beta-hydroxybutyrate and sodium S-beta-hydroxybutyrate;
racemic mixture of potassium R-beta-hydroxybutyrate and potassium S-beta-hydroxybutyrate,
A racemic mixture of calcium R-beta-hydroxybutyrate and calcium S-beta-hydroxybutyrate, or a racemic mixture of magnesium R-beta-hydroxybutyrate and magnesium S-beta-hydroxybutyrate. , the racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1. 12. The composition comprises a racemic mixture of beta-hydroxybutyrate salts from 80% to 99.7% by molar equivalents and a racemic mixture of beta-hydroxybutyrate from 20% to 0.3% by molar equivalents. Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition according to 1. 1 . The composition of claim 1 , wherein the composition comprises a racemic mixture of beta-hydroxybutyrate salts from 85% to 99.5% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid from 15% to 0.5% by molar equivalents. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition as described in . 2. The composition of claim 1, wherein the composition comprises 90% to 99% by molar equivalents of a racemic mixture of beta-hydroxybutyrate salts and 10% to 1% by molar equivalents of a racemic mixture of beta-hydroxybutyric acid. Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition. The racemic R,S-beta-hydroxybutyric acid of claim 1, further comprising at least one short chain fatty acid having less than 6 carbons, or a mono-, di-, or triglyceride of said at least one short chain fatty acid. Rate mixed salt-acid composition. 2. The method according to claim 1, further comprising at least one medium chain fatty acid having 6 to 12 carbons, such as 8 to 10 carbons, or a mono-, di- or triglyceride of said at least one medium chain fatty acid. Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition. fat burner supplements to increase lipolysis and/or fatty acid oxidation, or
The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, further comprising at least one of a nootropic supplement for enhancing cognitive performance, alertness, and/or mood. . The one or more fat burner supplements may include green tea, green tea extract, isolated green tea catechins, epigallocatechin gallate (EGCG), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), Coleus. forskohlii, yohimbine, rauwalsin, 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, noradrenaline reuptake inhibitors, hordenine, atomoxetine, 7-oxodehydroepiandrosterone, triiodothyronine, and 9. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 8 selected from the group consisting of combinations thereof. The at least one nootropic compound may include tyrosine, L-DOPA, tryptophan, 5-hydroxytryptophan, racetam, piracetam, oxiracetam, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine, Uptake inhibitors, hordenine, atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifo lia, Muira puama, Eschscholzia californica, Convolvulus pluricaulis, Centella asiatica (Centella asiatica), Evolvulus alsinoides, Bacopa mannieri, Epimedium herb, Ashwagandha herb, Ringed Ade nosine monophosphate (cAMP) modulator, forskolin, nicotine, caffeine, Racemic R according to claim 8, selected from the group consisting of amphetamine, coca leaf extract, cholinergic compounds, acetylcholine modulators, huperzine A, dimethylaminoethanol, choline, alpha-glycerophosphocholine, and combinations thereof. , S-beta-hydroxybutyrate mixed salt-acid composition. The racemic R,S-beta-hydroxybutyrate mixture of claim 1, further comprising a racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters. Salt-acid composition. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject, the composition comprising:
A racemic mixture of beta-hydroxybutyric acid comprising 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric acid, and 50% by enantiomeric equivalents of one or more R- a racemic mixture of beta-hydroxybutyrate salts comprising a beta-hydroxybutyrate salt and 50% by enantiomeric equivalent of one or more S-beta-hydroxybutyrate salts;
wherein the composition comprises a racemic mixture of beta-hydroxybutyrate salts from 75% to 99.9% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid from 25% to 0.1% by molar equivalents. ,
The beta-hydroxybutyrate salt is
Sodium R-beta-hydroxybutyrate,
Potassium R-beta-hydroxybutyrate,
R-beta-hydroxybutyrate calcium,
R-beta-hydroxybutyrate magnesium,
Sodium S-beta-hydroxybutyrate,
Potassium S-beta-hydroxybutyrate,
Calcium S-beta-hydroxybutyrate, and
S-beta-hydroxybutyrate magnesium;
The composition may be a tablet, capsule, powder, food, food additive, flavored beverage, vitamin-fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin-fortified beverage additive, non-alcoholic beverage additive, candy, bar. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition provided as or in a candies, troches, dietary supplements, flavored mouth sprays, or suppositories. 7. The composition comprises a racemic mixture of beta-hydroxybutyrate salts of 80% to 99.8% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid of 20% to 0.2% by molar equivalents. Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition according to Item 12. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone levels in a subject, the composition comprising:
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, troches, a dietary or pharmaceutically acceptable carrier selected from the group consisting of dietary supplements, flavored mouth sprays, and suppositories;
a racemic mixture of beta-hydroxybutyric acid comprising 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric acid;
Racemic mixture of beta-hydroxybutyrate salts comprising 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts including;
wherein the composition comprises a racemic mixture of beta-hydroxybutyrate salts from 75% to 99.9% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid from 25% to 0.1% by molar equivalents. ,
The beta-hydroxybutyrate salt is
Sodium R-beta-hydroxybutyrate,
Potassium R-beta-hydroxybutyrate,
R-beta-hydroxybutyrate calcium,
R-beta-hydroxybutyrate magnesium,
Sodium S-beta-hydroxybutyrate,
Potassium S-beta-hydroxybutyrate,
Calcium S-beta-hydroxybutyrate, and
A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition selected from magnesium S-beta-hydroxybutyrate. 7. The composition comprises a racemic mixture of beta-hydroxybutyrate salts from 80% to 99.7% by molar equivalents and a racemic mixture of beta-hydroxybutyric acid from 20% to 0.3% by molar equivalents. Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition according to 14. A kit for administering ketone bodies to a subject,
Racemic R,S-beta-hydroxybutyrate mixed salt-acid composition according to claim 1,
a container in which the composition is placed, and
A measuring device configured to hold therein a unit dose of said composition or a fraction thereof, wherein said unit dose of said composition contains about 0.5 g to about 25 g of a beta-hydroxybutyrate compound. A kit comprising a measuring device. 17. The kit of claim 16, wherein the container is selected from the group consisting of a carton, box, can, jar, bag, pouch, bottle, jug, and keg. 17. The kit of claim 16, wherein the measuring device is selected from the group consisting of a cup, scoop, syringe, dropper, spatula, spoon, and colon irrigation device. The composition allows administration of higher doses of the beta-hydroxybutyrate compound as compared to racemic R,S-beta-hydroxybutyrate salt compositions or racemic R,S-beta-hydroxybutyrate compositions. Racemic R,S-beta-hydroxybutyrate mixed salts according to claim 1, which are formulated to enable the development of side effects and/or to limit the occurrence and/or severity of side effects. Acid composition.

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