JP2023166026A - Non-racemic beta-hydroxybutyrate compounds, and compositions and kits enriched with r-enantiomer - Google Patents

Abstract

To provide ketogenic compositions and kits for increasing a ketone body level, including promoting and/or sustaining ketosis in a subject.SOLUTION: Ketogenic compositions and kits include a non-racemic mixture of beta-hydroxybutyrate salts and acids enriched with the R-enantiomer. They are rich in the R-enantiomer to elevate ketone bodies and increase the rate at which ketosis is achieved, and contain the S-enantiomer for other benefits. Beta-hydroxybutyric acid is rapidly absorbed and utilized by the body, enhances taste, and reduces the need to include other edible acids. Beta-hydroxybutyrate salts are slowly absorbed and utilized by the body and can provide one or more electrolytes. The non-racemic mixture in the composition contains about 50.5%-99.5% of R-beta-hydroxybutyrate and about 49.5%-0.5% of S-beta-hydroxybutyrate by enantiomeric equivalents.SELECTED DRAWING: None

Description

Described herein are mixed, non-racemic beta-hydroxybutyrate compounds, salts, acids, and esters thereof, and compositions enriched in the R-enantiomer of beta-hydroxybutyrate, and ketone bodies in a subject. Disclosed are uses in causing an increase in blood levels of.

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 through depletion of glucose stores in the body is 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 ends and the body leaves a state of ketosis, a state in which the body utilizes glucose as its primary fuel. , and the transition to ketosis must begin 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. The reduction in insulin levels due to ketosis also affects 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 racemic mixtures of beta-hydroxybutyrate (RS-beta-hydroxybutyrate or DL-beta-hydroxybutyrate). Other compositions, such as those by Lowery et al. disclosed in U.S. Patent Application Publication No. 2017/0296501, contain an endogenous form of beta-hydroxybutyrate, i.e. However, Lowery et al. do not recommend the use of non-endogenous enantiomers or S-beta-hydroxybutyrate. Other compositions, such as those disclosed in U.S. Pat. No. 8,642,654 to Clarke et al. - Consists mostly or entirely of hydroxybutyrate. Other enantiomers, such as (3R)-hydroxybutyl (3S)-hydroxybutyrate, (3S)-hydroxybutyl (3R)-hydroxybutyrate, and (3S)-hydroxybutyl (3S)-hydroxybutyrate, , largely or completely excluded. 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)
Disclosed herein are ketogenic compositions and methods for increasing ketone body levels in a subject, including promoting and/or sustaining ketosis in the subject. An exemplary composition comprises a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture is compared to S-beta-hydroxybutyrate enantiomers. is enriched with R-beta-hydroxybutyrate enantiomers, for example, R-beta-hydroxybutyrate enantiomer is enriched in enantiomeric equivalents from 50.5% to 99.5%, S-beta-hydroxybutyrate enantiomer is enriched in enantiomeric equivalents. The equivalent amount is 49.5% to 0.5%.

Non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate may be combined with S-beta-hydroxybutyrate to provide greater and/or faster ketogenic effects compared to racemic mixtures. It contains more R-beta-hydroxybutyrate enantiomers (ie, greater than 50% and less than 100%), which is the endogenous form produced by mammals, than rate enantiomers (ie, less than 50% and greater than 0%). The R-beta-hydroxybutyrate enantiomer is produced endogenously by mammals during ketosis, so when administered to a subject, the R-beta-hydroxybutyrate enantiomer can be used to produce energy (e.g. to replace glucose). (as a source of energy), resulting in additional amounts and/or increased plasma levels that can be readily utilized by the body.

Nevertheless, contrary to conventional wisdom to minimize or eliminate S-beta-hydroxybutyrate, which is not endogenously produced by mammals and is considered unnatural and potentially harmful, non- Racemic mixtures contain significant amounts of S-beta-hydroxybutyrate enantiomers to produce one or more desired effects in mammals, as described herein.

Additionally, conventional compositions typically include polymeric, oligomer, ester, or salt forms of beta-hydroxybutyrate, but are enriched in R-beta-hydroxybutyrate compared to S-beta-hydroxybutyrate. The non-racemic mixture may contain the free acid form of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. For example, a non-racemic mixture combines one or more salts or esters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with R-beta-hydroxybutyric acid, and optionally S-beta-hydroxybutyrate. may be included. Combining beta-hydroxybutyric acid with one or more beta-hydroxybutyrate salts reduces electrolyte load, increases absorption, improves taste, facilitates formulation, and has a neutral or acidic pH. It is beneficial because it reduces the need to add citric acid or other food acids to obtain the composition.

In some embodiments, the compositions disclosed herein provide a nutritionally or pharmaceutically effective amount of one or more compositions disclosed herein to a subject in need thereof. may be used in methods of increasing ketone body levels in a subject (including promoting and/or maintaining ketosis in a subject), including administering to a subject. 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, increased physical energy, and cognitive function. Improves traumatic brain injury, reduces the effects of diabetes, improves neuropathy, reduces cancer, reduces inflammation, anti-aging, anti-glycation, reduces epileptic seizures, improves mood, increases physical strength, muscle Includes one or more of an increase in volume or an improvement in body composition.

In some embodiments, R-beta-hydroxybutyrate is produced by administering a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomeric ratios or proportions disclosed herein. increase in endogenous production of S-beta-hydroxybutyrate and acetoacetate, endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate, Endogenous conversion to fatty acids and sterols, prolongation of ketosis, metabolism of S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate, increased fetal growth, growth years increase in 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 these may be provided.

The composition may include a nutritionally or pharmaceutically acceptable carrier.

That is, the invention according to this embodiment provides the following.

The invention according to this embodiment is a composition for administering ketone bodies to a subject, comprising R-beta-hydroxybutyrate of more than 50% and less than 100% in enantiomeric equivalent, and less than 50% and less than 100% in enantiomeric equivalent. a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, comprising greater than 0% S-beta-hydroxybutyrate; - said non-racemic mixture with hydroxybutyrate comprises at least one R-beta-hydroxybutyrate salt, at least one S-beta-hydroxybutyrate salt, and at least one of R- or S-beta-hydroxybutyrate; a non-racemic mixture comprising: a non-racemic mixture, wherein said composition is a powder;
Preferably, said non-racemic mixture comprises 50.5% to 99.5% R-beta-hydroxybutyrate by enantiomeric equivalent and 49.5% to 0.5% S-beta-hydroxybutyrate by enantiomeric equivalent. including,
The non-racemic mixture comprises 51% to 99% R-beta-hydroxybutyrate by enantiomeric equivalents and 49% to 1% S-beta-hydroxybutyrate by enantiomeric equivalents. The non-racemic mixture contains 52% to 98% R-beta-hydroxybutyrate and 48% to 2% S-beta-hydroxybutyrate by enantiomeric equivalent. - beta-hydroxybutyrate and 47% to 3% S-beta-hydroxybutyrate by enantiomeric equivalent;
The non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt of 90% to 99.9% by molar equivalent and 10% to 0.1% by molar equivalent. R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid,
The non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salts and S-beta-hydroxybutyrate salts of 94% to 99.5% by molar equivalents and 6% to 0.5% by molar equivalents. containing R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid,
The non-racemic mixture comprises a combination of 96% to 99% by molar equivalents of R-beta-hydroxybutyrate salts and S-beta-hydroxybutyrate salts, and 4% to 1% by molar equivalents of R-beta. - containing hydroxybutyric acid and/or S-beta-hydroxybutyric acid,
the non-racemic mixture comprises at least one lithium, sodium, potassium, calcium, magnesium, or amino acid salt of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate;
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,
Further comprising at least one supplement selected from vitamins, minerals, nootropics, and herbal supplements.

The invention according to this embodiment is a composition for administering ketone bodies to a subject, comprising R-beta-hydroxybutyrate of more than 50% and less than 100% in enantiomeric equivalent, and less than 50% and less than 100% in enantiomeric equivalent. a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, comprising greater than 0% S-beta-hydroxybutyrate; - said non-racemic mixture with hydroxybutyrate comprises at least one R-beta-hydroxybutyrate salt or ester, at least one S-beta-hydroxybutyrate salt or ester, and R- or S-beta-hydroxy a non-racemic mixture comprising at least one of butyric acid, the composition comprising a tablet, capsule, powder, food, food additive, flavored beverage, vitamin-enriched beverage, non-alcoholic beverage, flavored beverage additive. For compositions that are provided as or in a product, vitamin-enriched beverage additive, non-alcoholic beverage additive, candy, lollipop, lozenge, dietary supplement, flavored mouth spray, or suppository. ,
Preferably, said non-racemic mixture comprises 50.5% to 99.5% R-beta-hydroxybutyrate by enantiomeric equivalent and 49.5% to 0.5% S-beta-hydroxybutyrate by enantiomeric equivalent. including rate,
The non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salts and S-beta-hydroxybutyrate salts of 94% to 99.5% by molar equivalents and 6% to 0.5% by molar equivalents of containing R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid,
said non-racemic mixture comprises at least one lithium, sodium, potassium, calcium, magnesium, or amino acid salt of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate, and said composition the substance is powder,
Further comprising at least one supplement selected from vitamins, minerals, nootropics, and herbal supplements.

The invention according to this embodiment relates to a composition for administering ketone bodies to a subject, which includes tablets, capsules, powders, foods, food additives, flavored drinks, vitamin-enriched drinks, non-alcoholic drinks, and flavored drinks. A dietary or pharmaceutically acceptable additive selected from the group consisting of additives, vitamin-fortified beverage additives, non-alcoholic beverage additives, candies, lollipops, lozenges, dietary supplements, flavored mouth sprays, and suppositories. and more than 50% and less than 100% R-beta-hydroxybutyrate by enantiomeric equivalent and less than 50% and more than 0% S-beta-hydroxybutyrate by enantiomeric equivalent. - a non-racemic mixture of hydroxybutyrate and S-beta-hydroxybutyrate, wherein said non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains at least one R-beta - hydroxybutyrate salt or R-beta-hydroxybutyrate ester, at least one S-beta-hydroxybutyrate salt or S-beta-hydroxybutyrate ester, and R- or S-beta-hydroxybutyrate; a non-racemic mixture comprising at least one.

The invention according to this embodiment is a kit for administering ketone bodies to a subject, which comprises any of the above compositions, a container in which the composition is placed, and a unit dose of the composition or its fraction. a measuring device configured to hold a unit dose of said composition in about 0 minutes of said non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate; .5g to about 25g, a measuring device,
Preferably, said container is selected from the group consisting of a carton, box, can, jar, bag, pouch, bottle, jug, and keg.
The measuring device is selected from the group consisting of a cup, scoop, syringe, dropper, spatula, spoon, and colon irrigation device.

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.

（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. Introduction 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.

Unless otherwise specified, the term "salt" refers to any salt, such as a crystal, powder, or other solid form, that dissolves in water to form a solution, or disperses in a liquid to form a suspension or gel. 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.

In some cases, the composition may include a mixture of one or more beta-hydroxybutyrate salts and beta-hydroxybutyric acid. Providing R-beta-hydroxybutyrate in its acid form can be beneficial as the absorption response time is much more rapid compared to the salt form. Nevertheless, even though the acid form itself is a liquid with extremely low pH and unpalatable taste, it can be made or combined with a salt form and the amount of beta-hydroxybutyric acid in the salt form If relatively small, the composition may still form a solid, powder or other form typical of the salt form. In such cases, the salt and acid combination form of BHB has an acceptable pH and taste. BHB compositions containing both salt and acid forms offer improved absorption, increased bioavailability, reduced electrolyte loading, ease of manufacture, significantly improved taste, and compositions with neutral or acidic pH. Benefits include reduced need for citric acid or other edible acids to obtain food. It will also be appreciated that mixtures of salts and/or esters of BHB and acid forms of BHB may also be used to beneficial effect.

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 the molar equivalents of (i) non-deprotonated beta-hydroxybutyric acid molecules in solution. 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 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 the pH of the solution.

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

Beta-hydroxybutyrate, typically the endogenous form, R-beta-hydroxybutyrate, is produced when glucose levels in a subject are low or when the patient's body has a usable form of beta-hydroxybutyrate. When supplemented, 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.

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 of the product or a component thereof or a fraction 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.

As used herein, "ketosis" refers to a subject having blood ketone levels within the range of about 0.5 mmol/L to about 16 mmol/L. Ketosis can improve mitochondrial function, reduce 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 may nevertheless increase energy production and/or other effects of ketone bodies. It means an increase in the supply of ketones to exert beneficial effects. For example, a "ketone adapted" subject may not necessarily have elevated serum levels of ketone bodies, but they will have a more rapid rise in ketone body serum levels compared to a non-ketone adapted subject. , can rather utilize the available ketone bodies. 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 plasma levels.

The term "short chain triglycerides" (SCT) refers to molecules that have a glycerol backbone with three medium chain fatty acids attached. Short chain fatty acids can range from 2 to 5 carbon atoms in length. Examples of short chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and the like. Examples of SCTs include tributyrin.

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

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

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).

II. Non-racemic beta-hydroxybutyrate compositions Compositions for increasing ketone body levels in a subject, including promoting and/or maintaining ketosis, include R-beta-hydroxybutyrate enriched in the R-enantiomer. A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate (i.e., more than 50% and less than 100% enantiomeric equivalents of R-beta-hydroxybutyrate, and less than 50% and more than 0% S-beta-hydroxy by enantiomeric equivalents) butyrate).

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is 50.5% to 99.5%, 51% to 99%, 52% by enantiomeric equivalent. Contains ~98%, 53%-97%, 55%-95%, 55%-89%, 57%-87%, or 60%-80% of the R-beta-hydroxybutyrate enantiomer, with an enantiomeric equivalent of 49 .5% to 0.5%, 49% to 1%, 48% to 2%, 47% to 3%, 45% to 5%, 45% to 11%, 43% to 13%, 41% to 15% , or 40% to 20% of the S-beta-hydroxybutyrate enantiomer.

Non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate may be combined with S-beta-hydroxybutyrate to provide greater and/or faster ketogenic effects compared to racemic mixtures. It contains more R-beta-hydroxybutyrate enantiomer, which is the endogenous form produced by mammals, than the rate enantiomer. Since the R-beta-hydroxybutyrate enantiomer is endogenously produced by mammals during ketosis, administering the R-beta-hydroxybutyrate enantiomer to a subject can produce R,S-beta-hydroxybutyrate ( (Also known as: DL-beta-hydroxybutyrate) provides an additional amount that is readily available to the body, such as for energy production (e.g. as an energy source to replace glucose) and/or to the blood plasma. Level increases. This effect can be modulated and extended by the presence of the S-enantiomer.

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

Non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be used for purposes such as, but not limited to, appetite suppression, weight loss, fat loss, lowering blood glucose levels, and mental alertness. Improves sexuality, 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, epileptic seizures It can be used to produce one or more desired effects in a subject, including reducing stress, improving mood, increasing physical strength, increasing muscle mass, or improving body composition.

The composition may include a nutritionally or pharmaceutically acceptable carrier.

R-beta-hydroxybutyrate and S-beta-hydroxybutyrate may be provided in various forms such as salts and/or esters, along with an amount of the free acid form. The percent enantiomeric equivalents for each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate are R-beta-hydroxybutyrate divided by the total molar amount of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. Defined as the molar amount of either hydroxybutyrate or S-beta-hydroxybutyrate. Any salt-forming cations and/or ester-forming alcohol amounts are excluded in determining the percent enantiomeric equivalent ratio for each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. It is not included in the calculation. For example, the weight of cations, alcohols, complexing agents, etc. can be taken into account so as not to affect the enantiomeric equivalents of R-BHB and S-BHB.

The composition comprises R-beta-hydroxybutyrate and large amounts of precursors, namely R-1,3-butanediol and R-beta-hydroxybutyrate monomers, which are easily converted to R-beta-hydroxybutyrate. In order to avoid overloading with the ester (i.e. (3R)-hydroxybutyl (3R)-hydroxybutyrate monoester), the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is , (3R)-hydroxybutyl (3R)-hydroxybutyrate monoester by enantiomeric equivalents of 88%, or 87%, or 86%, or 85%.

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is provided in a composition that includes a dietetically or pharmaceutically acceptable carrier. . Examples include powders, liquids, tablets, capsules, foods, food additives, beverages, beverage additives, candies, lollipops, troches, dietary supplements, sprays, injections, and suppositories.

In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is an alkali metal, an alkaline earth metal, a transition metal, an amino acid, or one of the metabolites of the amino acid. It may be provided as a salt, such as the above salts. 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.

Non-racemic mixtures of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate can be provided as one or more esters such as mono-, di-, tri-, oligo-, and polyesters. For example, 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)-monoester of hydroxybutyrate, (3R)-hydroxybutyl (3S)-monoester of hydroxybutyrate, diester of glycerin, triester of glycerin, ester of acetoacetate, beta-hydroxybutyrate dimers, trimers, oligomers, and polyesters having repeating units of beta-hydroxybutyrate and one or more of lactic acid, citric acid, acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, and with other hydroxycarboxylic acids such as malic acid, and/or beta-hydroxybutyrate with one or more diols such as 1,3-propanediol and 1,3-butanediol, and one or more tartaric acid. , citric acid, malic acid, succinic acid, and polyacids such as fumaric acid. (3R)-Hydroxybutyl (3R)-hydroxybutyrate monoester may be included, but not more than 88%, or 87%, or 86%, or 85% by enantiomeric equivalent of the composition.

Said non-racemic mixture comprises one or more salt forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in a relatively small amount of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. may be included in combination with the acid form of the acid. The ratio of salt form to acid form of R-beta-hydroxybutyrate is not necessarily the same as the ratio of salt form to acid form of S-beta-hydroxybutyrate. This provides greater flexibility and broader advantages in controlling the pharmacokinetics and electrolyte balance of the composition.

In some embodiments, the non-racemic mixture comprises less than 100% of one or more beta-hydroxybutyrate salts and more than 0% free beta-hydroxybutyric acid, e.g., up to 99.9% in molar equivalents. , 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98 .65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and at least 75%, 80%, 85 %, 90%, 92%, 94%, 95%, 96%, or 97% of one or more R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate salts, and molar equivalents of at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1. 2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%, 25%, Contains less than 20%, 15%, 10%, 8%, 6%, 5%, 4%, or 3% free R-beta-hydroxybutyric acid and/or free S-beta-hydroxybutyric acid.

If the non-racemic mixture contains a large amount of the R-enantiomer compared to the S-enantiomer, even if a higher proportion of free S-beta-hydroxybutyric acid is used compared to the S-beta-hydroxybutyrate salt; It is possible to obtain compositions with neutral or other desired pH. That is, even if the relative amount of S-beta-hydroxybutyrate is high compared to the S-beta-hydroxybutyrate salt, if the amount of R-beta-hydroxybutyrate salt is high, the overall amount of acid is relatively small. There is a possibility that it will become less.

In other embodiments, the non-racemic mixture comprises R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with a relatively small amount of the acid form of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. It may contain one or more ester forms of beta-hydroxybutyrate. In yet other embodiments, the non-racemic mixture contains both salt and ester forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in relatively small amounts of R-beta-hydroxybutyrate. and/or in combination with the acid form of S-beta-hydroxybutyrate.

In some embodiments, the composition may include at least one medium chain fatty acid, or a mono-, di-, or triglyceride of at least one medium chain fatty acid, wherein the medium chain fatty acid has 6 to 12 , preferably 8 to 10 carbons. The composition may include at least one short chain fatty acid, or a mono-, di-, or triglyceride of the at least one short chain fatty acid, wherein the short chain fatty acid has less than 6 carbons. Less preferably, the composition may comprise at least one long chain fatty acid having more than 12 carbons or a mono-, di- or triglyceride of said long-chain fatty acid.

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

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 non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate increases and sustains blood levels of ketone bodies, thereby contributing to the metabolic and physiological effects of sustained ketosis. You can take advantage of it. compared to methods that aim to induce and maintain ketosis based solely on diet (e.g., fasting and/or restricting carbohydrate intake) by increasing blood levels of ketone bodies. You will have more flexibility in your food choices. For example, a subject administered an appropriate amount of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate returns to a ketogenic state and a glucose-based metabolic state without endangering the ketogenic state. You will now be able to occasionally consume carbohydrate- or sugar-based foods without having to do so. 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. 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 bad taste of the beta-hydroxybutyrate compound. 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. 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.

By administering a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomeric ratios or proportions described herein, the endogenous source of R-beta-hydroxybutyrate and acetoacetate can be reduced. increased sexual production, endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate, endogenous conversion of S-beta-hydroxybutyrate to fatty acids and sterols. sex conversion, prolongation of ketosis, metabolism of S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate, increased fetal development, increased growth years, acetone during ketosis. one or more of the following: reduction in endogenous production of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to regulate glucose metabolism, antioxidant activity, and production of acetyl-CoA. Ru.

The ketogenic compositions described herein can be administered to a subject in a therapeutically effective amount and/or at a frequency that induces or maintains ketosis. In some embodiments, a single dose 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 to about Includes an amount of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate ranging from 12 grams.

In some embodiments, 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.

In some embodiments, the ketone bodies described herein are used to maintain ketosis for a longer period of time compared to the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate per se. The composition may contain one or more short-chain fatty acids, medium-chain fatty acids, long-chain fatty acids, fatty acid esters, or mono-, di-, short-, medium-, or long-chain fatty acids. , or may further contain triglyceride. In some embodiments, the composition preferably comprises a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and a short, medium, or long chain fatty acid (or ester) in the range of about 4:1 to about 1:4, or about 2:1 to about 1:2, or about 1.5:1 to about 1:1.5. Ru.

In some embodiments, the subject preferably follows a ketogenic diet that limits carbohydrate and protein intake during the period of administration of the composition. For example, 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 preferred embodiments, the ketogenic compositions are administered orally in powder form, such as solid and/or powder mixtures (e.g., powder-filled gelatin capsules), tightly pressed tablets, or other oral routes of administration known in the art. may be done.

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 pretreatment, 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 dosage 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's 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 composition 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 Below are exemplary non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate compositions and other ketogenic compositions useful for increasing ketone levels in a subject. are described and include inducing and/or 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.

In some cases, the compositions include a mixture of beta-hydroxybutyrate salts, a mixture of beta-hydroxybutyrate esters, Mixtures of beta-hydroxybutyrate salts and esters, mixtures of beta-hydroxybutyrate salts and free beta-hydroxybutyric acid, mixtures of beta-hydroxybutyrate esters and free beta-hydroxybutyrate, or beta-hydroxybutyrate It may also be a mixture of salts, beta-hydroxybutyrate esters, and free beta-hydroxybutyric acid. The compositions also contain short, medium, or long chain fatty acids, esters, glycerides, and other fatty acids as disclosed herein to provide the desired elevated levels of ketone bodies and other effects. may be mixed with supplements.

Example 1
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 51% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 49% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose the onset of ketosis is accelerated compared to the same dose of the racemic mixture. On the other hand, inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer period of ketosis and/or other benefits disclosed herein.

Said non-racemic mixture is readily administered as a ketogenic composition, 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. .

Example 2
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 52% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 48% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose the onset of ketosis is accelerated compared to the same dose of the racemic mixture. On the other hand, inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer period of ketosis and/or other benefits disclosed herein.

Example 3
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 53% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 47% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose the onset of ketosis is accelerated compared to the same dose of the racemic mixture. On the other hand, inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer period of ketosis and/or other benefits disclosed herein.

Example 4
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 55% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 45% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose the onset of ketosis is accelerated compared to the same dose of the racemic mixture. On the other hand, inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer period of ketosis and/or other benefits disclosed herein.

Example 5
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 57% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 43% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, ketosis is less likely to occur compared to the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-4. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 6
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 59% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 41% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, the development of ketosis is less likely than with the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-5. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 7
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 65% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 35% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, the development of ketosis is less likely than with the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-6. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 8
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 70% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 30% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, the development of ketosis is less likely than with the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-7. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 9
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 75% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 25% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, the development of ketosis is less likely than with the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-8. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 10
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 80% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 20% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, the development of ketosis is less likely than with the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-9. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 11
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 85% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 15% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, ketosis is less likely to occur compared to the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-10. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 12
R-beta-hydroxybutyrate and S-beta by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. -Hydroxybutyrate to provide 89% of the R-beta-hydroxybutyrate enantiomer by enantiomeric equivalents and 11% of the S-beta-hydroxybutyrate enantiomer by enantiomeric equivalents. Because the non-racemic mixture contains more R-beta-hydroxybutyrate enantiomer, at a given dose, ketosis is less likely to occur compared to the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-11. It's early. On the other hand, by containing the S-beta-hydroxybutyrate enantiomer, a longer-term ketosis state and/or Other benefits will accrue as disclosed in the book.

Example 13
R-beta-hydroxybutyrate and S-beta-hydroxybutyrate by mixing one or more R-beta-hydroxybutyrate compounds and a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate compositions. - prepare non-racemic mixtures with beta-hydroxybutyrate, with enantiomeric equivalents of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 99 .5% of the R-beta-hydroxybutyrate enantiomer, and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% by enantiomeric equivalent. Provides 5% S-beta-hydroxybutyrate enantiomer. provided that the non-racemic mixture contains, by enantiomeric equivalent, 88%, or 87%, or 86%, or more than 85% (3R)-hydroxybutyl (3R)-hydroxybutyrate monoester (i.e., R-1, monoester of 3-butanediol and R-beta-hydroxybutyrate). Said non-racemic mixture contains more of the R-beta-hydroxybutyrate enantiomer and therefore, at a given dose, ketosis occurs faster compared to the same dose of the racemic mixture or the non-racemic mixtures of Examples 1-12. .

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

Example 15
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is combined with one or more medium chain triglycerides and/or one or more medium chain fatty acids and/or one or more medium chain fatty acids monomer. - or diglycerides, any of the foregoing examples are modified.

Example 16
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is combined with one or more short chain triglycerides and/or one or more short chain fatty acids and/or one or more short chain fatty acids monomer. - or diglycerides, any of the foregoing examples are modified.

Example 17
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is combined with one or more long chain triglycerides and/or one or more long chain fatty acids and/or monomers of one or more long chain fatty acids. - or diglycerides, any of the foregoing examples are modified.

Example 18
The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is combined with one or more dietary supplements such as vitamin D ₃ , vitamins, minerals and other dietary supplements known in the art. In combination, any of the above embodiments is modified.

Example 19
Any of the foregoing examples may include one or more salts of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-hydroxybutyric acid or S-beta-hydroxybutyrate. to provide a mixture of R- and S-beta-hydroxybutyrate salts and free R- and/or S-beta-hydroxybutyric acid. wherein said mixture comprises less than 100% of one or more beta-hydroxybutyrate salts and more than 0% free beta-hydroxybutyric acid, up to 99.9%, 99.8%, 99. 7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5% , 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97% of one or more R-beta-hydroxybutyrate and/or S-beta - contains hydroxybutyrate salts, at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8 in molar equivalents %, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2. Contains 75%, or 3% free R-beta-hydroxybutyric acid and/or free S-beta-hydroxybutyric acid.

Example 20
Any of the foregoing examples include one or more esters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid. modified to provide a mixture of ester forms of R- and S-beta-hydroxybutyrate and free R- and/or S-beta-hydroxybutyric acid. Here, the non-racemic mixture contains less than 100% of one or more beta-hydroxybutyrate esters and more than 0% free beta-hydroxybutyrate.

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 (22)

A composition for administering ketone bodies to a subject, the composition comprising:
R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, including more than 50% and less than 100% R-beta-hydroxybutyrate by enantiomeric equivalent and less than 50% and more than 0% S-beta-hydroxybutyrate by enantiomeric equivalent. - a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, said non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate;
at least one R-beta-hydroxybutyrate salt;
a non-racemic mixture comprising at least one S-beta-hydroxybutyrate salt and at least one of R- or S-beta-hydroxybutyrate;
wherein the non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt in molar equivalents of 99.6% or more and less than 100%, and
The composition, wherein the non-racemic mixture contains at least one of R- or S-beta-hydroxybutyric acid in a molar equivalent amount of more than 0% and less than or equal to 0.4%. the non-racemic mixture comprising 50.5% to 99.5% R-beta-hydroxybutyrate by enantiomeric equivalent and 49.5% to 0.5% S-beta-hydroxybutyrate by enantiomeric equivalent; A composition according to claim 1. The composition of claim 1, wherein the non-racemic mixture comprises 51% to 99% R-beta-hydroxybutyrate by enantiomeric equivalent and 49% to 1% S-beta-hydroxybutyrate by enantiomeric equivalent. . The composition of claim 1, wherein the non-racemic mixture comprises 52% to 98% R-beta-hydroxybutyrate by enantiomeric equivalent and 48% to 2% S-beta-hydroxybutyrate by enantiomeric equivalent. . The composition of claim 1, wherein the non-racemic mixture comprises 53% to 97% R-beta-hydroxybutyrate by enantiomeric equivalent and 47% to 3% S-beta-hydroxybutyrate by enantiomeric equivalent. . The non-racemic mixture is a combination of R-beta-hydroxybutyrate salts and S-beta-hydroxybutyrate salts of more than 99.6% and less than 100% by molar equivalents, and more than 0% by molar equivalents and 0.4% by molar equivalents. A composition according to claim 1, comprising less than R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid. The non-racemic mixture is a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt of 99.7% or more and less than 100% in molar equivalents, and more than 0% and 0.3% in molar equivalents. The composition according to claim 1, comprising: R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid. The non-racemic mixture is a combination of R-beta-hydroxybutyrate salts and S-beta-hydroxybutyrate salts of more than 99.7% and less than 100% by molar equivalents, and more than 0% by molar equivalents and 0.3% by molar equivalents. A composition according to claim 1, comprising less than R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid. 4. The non-racemic mixture comprises at least one lithium, sodium, potassium, calcium, magnesium, or amino acid salt of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. 1. The composition according to 1. 2. The composition of claim 1, further comprising at least one fatty acid, or a mono-, di-, or triglyceride of said at least one fatty acid. 2. The composition of claim 1, further comprising at least one supplement selected from vitamins, minerals, nootropics, and herbal supplements. A composition for administering ketone bodies to a subject, the composition comprising:
R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, comprising more than 50% but less than 100% R-beta-hydroxybutyrate by enantiomeric equivalent and less than 50% and more than 0% S-beta-hydroxybutyrate by enantiomeric equivalent. a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprising:
at least one R-beta-hydroxybutyrate salt or ester;
at least one S-beta-hydroxybutyrate salt or ester, and
a non-racemic mixture comprising at least one of R- or S-beta-hydroxybutyric acid;
wherein the non-racemic mixture comprises a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt in molar equivalents of 99.6% or more and less than 100%, and
The non-racemic mixture contains at least one of R- or S-beta-hydroxybutyric acid in a molar equivalent amount of more than 0% and not more than 0.4%,
The composition can be used as tablets, capsules, powders, foods, food additives, flavored beverages, vitamin-fortified beverages, non-alcoholic beverages, flavored beverage additives, vitamin-fortified beverage additives, non-alcoholic beverage additives, candies, bars. Compositions provided as or in candies, lozenges, dietary supplements, flavored mouth sprays, or suppositories. The non-racemic mixture comprises 50.5% to 99.5% R-beta-hydroxybutyrate by enantiomeric equivalent and 49.5% to 0.5% S-beta-hydroxybutyrate by enantiomeric equivalent. 13. The composition of claim 12. The non-racemic mixture is a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt of 99.6% or more and less than 100% in molar equivalents, and more than 0% and 0.4% in molar equivalents. The composition according to claim 12, comprising: R-beta-hydroxybutyric acid and/or S-beta-hydroxybutyric acid. said non-racemic mixture comprises at least one lithium, sodium, potassium, calcium, magnesium, or amino acid salt of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate, and said composition 13. The composition of claim 12, wherein the product is a powder. 13. The composition of claim 12, further comprising at least one supplement selected from vitamins, minerals, nootropics, and herbal supplements. A composition for administering ketone bodies to 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; and
R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, comprising more than 50% but less than 100% R-beta-hydroxybutyrate by enantiomeric equivalent and less than 50% and more than 0% S-beta-hydroxybutyrate by enantiomeric equivalent. a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprising:
at least one R-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate ester;
at least one S-beta-hydroxybutyrate salt or S-beta-hydroxybutyrate ester, and
a non-racemic mixture comprising at least one of R- or S-beta-hydroxybutyric acid;
Here, the non-racemic mixture includes a combination of R-beta-hydroxybutyrate salt and S-beta-hydroxybutyrate salt in a molar equivalent of 99.6% or more and less than 100%, and
A composition wherein the non-racemic mixture contains from more than 0% to less than 0.4% by molar equivalent of at least one of R- or S-beta-hydroxybutyric acid. A kit for administering ketone bodies to a subject,
The 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 comprises R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. a measuring device comprising about 0.5 g to about 25 g of said non-racemic mixture with. 19. The kit of claim 18, wherein the container is selected from the group consisting of a carton, box, can, jar, bag, pouch, bottle, jug, and keg. 19. The kit of claim 18, wherein the measuring device is selected from the group consisting of a cup, scoop, syringe, dropper, spatula, spoon, and colon irrigation device. The composition according to claim 1, wherein the war composition is a powder. 13. The composition of claim 12, further comprising at least one fatty acid or a mono-, di-, or triglyceride of said fatty acid.