CN114025752A - R-enantiomer enriched non-racemic beta-hydroxybutyrate compounds and compositions and methods of use - Google Patents
R-enantiomer enriched non-racemic beta-hydroxybutyrate compounds and compositions and methods of use Download PDFInfo
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- CN114025752A CN114025752A CN202080013807.2A CN202080013807A CN114025752A CN 114025752 A CN114025752 A CN 114025752A CN 202080013807 A CN202080013807 A CN 202080013807A CN 114025752 A CN114025752 A CN 114025752A
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- Prior art keywords
- hydroxybutyrate
- beta
- composition
- racemic mixture
- enantiomeric
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
Abstract
A ketogenic composition comprising a non-racemic mixture of R-enantiomer enriched beta-hydroxybutyrate and an acid. The compositions are enriched in the R-enantiomer to increase ketone bodies and increase the rate at which ketosis is achieved, and further comprise an amount of the S-enantiomer to provide an alternative benefit. Beta-hydroxybutanoic acid is absorbed and utilized by the body more rapidly than salts or esters, enhances taste, and reduces the need to include citric or other edible acids. Beta-hydroxybutyrate is absorbed and utilized more slowly by the body and may provide one or more electrolytes. A composition for increasing ketone body levels in a subject can comprise a dietary or pharmaceutically acceptable carrier and a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprises about 50.5% to 99.5% by enantiomeric equivalent of R-beta-hydroxybutyrate and about 49.5% to about 0.5% by enantiomeric equivalent of S-beta-hydroxybutyrate.
Description
Background
1. Field of the invention
Disclosed herein are mixed non-racemic β -hydroxybutyrate compounds enriched in the R-enantiomer of β -hydroxybutyrate, salts, acids and esters thereof, and compositions and uses thereof to produce elevated blood levels of ketone bodies in a subject.
2. Correlation technique
During fasting, extreme exercise, and/or low carbohydrate consumption, the in vivo glucose and glycogen stores are rapidly utilized and may become rapidly depleted. When glucose stores become depleted, failure to replenish glucose stores results in the body's metabolic shift to production and utilization of ketone bodies for energy ("ketosis"). Ketone bodies can be used as fuel by cells of the body to meet the energy needs of the body, including the brain and heart. For example, blood ketone levels can be increased to 2 to 3mmol/L or more during a long fasting period. It is generally understood that when blood ketones rise above 0.5mmol/L, heart, brain and peripheral tissues use ketone bodies (e.g., beta-hydroxybutyrate and acetoacetate) as the primary fuel source. This condition is called ketosis. At blood levels of 1.0mmol/L to 3.0mmol/L, this condition is termed "ketotrophy".
At the transition to ketosis, or in other words, during ketogenic metabolism of the liver, the body uses dietary and body fat as the main energy source. Thus, once ketosis occurs, ketosis can be maintained by controlling dietary fat intake and maintaining low carbohydrate intake and blood levels, resulting in loss of body fat.
During ketosis, the body is in ketogenesis and essentially burns fat for its primary fuel. The body breaks down fat into fatty acids and glycerol and converts the fatty acids into acetyl-CoA molecules, which are then ultimately converted in the liver by ketogenesis into the water-soluble ketone bodies beta-hydroxybutyrate (i.e., "beta-hydroxybutyrate" or "BHB"), acetoacetate (also known as acetylacetone) and acetone. Beta-hydroxybutyrate and acetoacetate are the major ketone bodies used by the body for energy, while acetone is removed and excreted as a by-product of ketogenesis.
The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle sparing (muscle sparing) properties, and improved cognitive and physical performance. Scientific-based improvements in the efficacy of cellular metabolism through ketone supplementation management can beneficially affect physical, cognitive and mental health, and have long-term effects on health against common avoidable diseases (e.g., obesity, cardiovascular disease, neurodegenerative disease, diabetes and cancer).
Despite the many health advantages of seeking ketogenic diets or lifestyles and maintaining nutritional ketosis status, there are significant obstacles to seeking and maintaining ketogenic status. One of these obstacles is the difficulty of transitioning to the ketogenic state. The fastest endogenous way to enter ketosis by depleting glucose stores in the body is by combining fasting. This is a physical and emotional requirement and is extremely challenging even for the most motivated and autonomous people.
In addition, the transition to ketosis is often accompanied by hypoglycemia, which in many people can lead to somnolence and dizziness, resulting in uncomfortable physiological and mental states, commonly referred to as "low-carbohydrate flu (low-carb flu)". In addition, many people experience down-regulation of their metabolism as the body naturally enters an "energy-saving" mode. Some believe that these transient symptoms can last for up to two to three weeks. During this transition period, if the subject consumes a meal or snack containing more than a limited amount of carbohydrates, ketogenesis immediately terminates, the body exits its ketosis state as the body transfers back to utilizing glucose for its primary fuel, and the transition to ketosis must resume.
Maintaining ketosis behavior is also difficult, if not more difficult, if the subject is successful in establishing ketosis, because of the need to maintain strict dietary ratios of carbohydrates and proteins to fat. Further complicating this is the disruption of normal electrolyte balance that typically occurs when transitioning to and maintaining the ketogenic state. Depletion and reduced glycogen stores in the liver and muscle reduce the body's ability to retain water, leading to more frequent urination and, correspondingly, greater electrolyte loss. In addition, the decrease in insulin levels caused by ketosis affects the rate at which kidneys extract certain electrolytes, thereby reducing electrolyte levels in the body. Negative effects of electrolyte imbalance include muscle pain, spasticity, convulsions and weakness, restlessness, anxiety, frequent headaches, feeling very thirsty, insomnia, fever, palpitations or arrhythmia, digestive problems (e.g., spasticity, constipation or diarrhea), confusion and inattention, bone disorders, joint pain, changes in blood pressure, changes in appetite or weight, fatigue (including chronic fatigue syndrome), joint numbness, and dizziness (particularly when standing suddenly).
Some compositions for promoting ketosis in a mammal comprise a racemic mixture of beta-hydroxybutyrate (RS-beta-hydroxybutyrate or DL-beta-hydroxybutyrate). Other compositions, such as those disclosed in U.S. patent publication No.2017/0296501 to Lowery et al, contain endogenous forms of beta-hydroxybutyrate or R-beta-hydroxybutyrate, while Lowery et al discourages the use of non-endogenous enantiomers or S-beta-hydroxybutyrate. Others, such as those disclosed in U.S. patent No.8,642,654 to Clarke et al, consist primarily or entirely of a single β -hydroxybutyrate (3R) -hydroxybutyl (3R) -hydroxybutyrate. The other enantiomers, such as (3R) -hydroxybutyl (3S) -hydroxybutyrate, (3S) -hydroxybutyl (3R) -hydroxybutyrate and (3S) -hydroxybutyl (3S) -hydroxybutyrate, are largely or entirely omitted. Ignoring enantiomers that are not endogenous forms of beta-hydroxybutyrate is based on the insight that S-beta-hydroxybutyrate (also known as (3S) -hydroxybutyrate) is ineffective or even detrimental.
Summary of The Invention
Disclosed herein are ketogenic compositions and methods for increasing ketone body levels in a subject, including promoting and/or maintaining ketosis in a subject. An exemplary composition comprises a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture is enriched in the R-beta-hydroxybutyrate enantiomer relative to the S-beta-hydroxybutyrate enantiomer, for example 50.5% to 99.5% R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 49.5% to 0.5% S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent.
The non-racemic mixture of R- β -hydroxybutyrate and S- β -hydroxybutyrate contains more of the R- β -hydroxybutyrate enantiomer (i.e. greater than 50% and less than 100%) than the S- β -hydroxybutyrate enantiomer (i.e. less than 50% and greater than 0%) (the endogenous form produced by the mammal) compared to the racemic mixture to provide a greater and/or faster ketogenic effect. Because the R-13-hydroxybutyrate enantiomer is endogenously produced by the mammal during ketosis, administration of the R- β -hydroxybutyrate enantiomer to a subject provides additional amounts and/or increased plasma levels that are immediately available to the body, for example, for energy production (e.g., as an alternative energy source to glucose).
Nonetheless, and contrary to conventional wisdom of minimizing or eliminating S- β -hydroxybutyrate (which is not endogenously produced by mammals and is believed to be non-natural and potentially harmful), the non-racemic mixture comprises a significant amount of the S- β -hydroxybutyrate enantiomer to produce one or more desired effects in mammals as discussed herein.
Additionally, while conventional compositions typically comprise a polymer, oligomer, ester, or salt form of beta-hydroxybutyrate, a non-racemic mixture enriched in R-beta-hydroxybutyrate relative to S-beta-hydroxybutyrate may comprise the free acid form of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. For example, the non-racemic mixture may comprise one or more salts or esters of R- β -hydroxybutyrate and S- β -hydroxybutyrate in combination with R- β -hydroxybutyrate and optionally S- β -hydroxybutyrate. Combining beta-hydroxybutyrate with one or more beta-hydroxybutyrate salts is beneficial because it reduces electrolyte loading, increases absorption, improves taste, facilitates easier formulation, and reduces the need to add citric acid or other food acids to obtain a composition with a neutral or acidic pH.
In some embodiments, the compositions disclosed herein may be used in a method for increasing ketone body levels in a subject (including promoting and/or maintaining ketosis in a subject) comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of one or more compositions disclosed herein. Some examples of beneficial effects of elevated ketone body levels in a subject include one or more of the following: appetite suppression, weight loss, fat loss, reduced blood glucose levels, improved mental alertness, increased body energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.
In some embodiments, administering a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the ratio or percentage of enantiomers disclosed herein provides one or more of the following: increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; endogenous transformation 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; prolongation of ketosis; the metabolism of S-beta-hydroxybutyrate is independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate; an increase in fetal development; the growth years are increased; reduced endogenous production of acetone during ketosis; (ii) signaling through S-beta-hydroxybutyrate, which regulates R-beta-hydroxybutyrate and glucose metabolism; antioxidant activity; and production of acetyl CoA.
The composition may comprise a nutritionally or pharmaceutically acceptable carrier.
Additional features and advantages will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing summary of the invention and the following detailed description of the invention are exemplary and explanatory only and are not restrictive of the embodiments disclosed or claimed herein.
Detailed Description
I. Brief introduction to the drawings
The compound "beta-hydroxybutyrate", also known as beta-hydroxybutyrate, 3-hydroxybutyrate, beta HB or BHB, is a deprotonated form of beta-hydroxybutyrate, which is of the general formula CH3CH2OHCH2Hydroxy carboxylic acid of COOH. The deprotonated form present at typical biological pH levels is CH3CH2OHCH2COO-. The general chemical structure shown below represents a β -hydroxybutyrate compound useful in the disclosed compositions:
wherein the content of the first and second substances,
x may be hydrogen, a metal ion, an amino cation (e.g. from an amino acid), an alkyl, alkenyl, aryl or acyl group.
When X is hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is beta-hydroxybutyrate. When X is alkyl, alkenyl, aryl or acyl, the compound is beta-hydroxybutyrate. The aforementioned compounds may be in any desired physical form, such as crystals, powders, solids, liquids, solutions, suspensions or gels.
Unless otherwise specified, the term "salt" does not mean or imply any particular physical state of being dissolved in water to form a liquid solution, dispersed in a liquid to form a suspension, or a gel, such as crystalline, powder, other solid forms. Salts may be formed in solution, for example, by at least partially neutralizing beta-hydroxybutyrate with strong or weak bases such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, basic amino acids, and the like.
In some cases, the composition may comprise a mixture of one or more beta-hydroxybutyrate and one or more beta-hydroxybutyrate. Providing R- β -hydroxybutyrate in its acid form may be beneficial because its absorption response time is much faster than in the salt form. Nevertheless, even if the acid form itself is a liquid with a very low pH and an unpleasant taste, the composition may form a solid, powder or other typical form of the salt form when prepared or combined with the salt form and wherein the amount of beta-hydroxybutyrate is small relative to the salt form. In such cases, the combined salt and acid forms of BHB have an acceptable pH and taste. BHB compositions comprising both salt and acid forms have advantages such as: increased absorption, increased bioavailability, reduced electrolyte load, ease of manufacture, significant taste improvement, and reduced need for citric acid or other edible acids to obtain a composition with a neutral or acidic pH. It is understood that the use of a mixture of BHB salts and/or ester and acid forms of BHB may also provide beneficial effects.
The term "free β -hydroxybutyrate" means the sum of the non-deprotonated and deprotonated β -hydroxybutyrate molecules. Deprotonated β -hydroxybutyrate molecules generally mean that a proton has been released to form the hydronium ion (H)3O +) and beta-hydroxybutyrate anion (e.g., dissolved in water).
When the free beta-hydroxybutyrate molecule is included in the beta-hydroxybutyrate mixed salt-acid composition as a dry powder or other solid form, it is typically not deprotonated to any significant extent. In such cases, the fractional amount of free beta-hydroxybutyrate in the mixed salt-acid composition of beta-hydroxybutyrate on a weight basis is the weight of free beta-hydroxybutyrate divided by the combined weight of free beta-hydroxybutyrate and beta-hydroxybutyrate. The fractional amount of free beta-hydroxybutyrate in the hybrid salt-acid composition on a molar basis is the molar equivalent of free beta-hydroxybutyrate divided by the sum of the molar equivalents of free beta-hydroxybutyrate and the molar equivalents of beta-hydroxybutyrate anion provided by the beta-hydroxybutyrate.
When dissolved in water, a portion of the beta-hydroxybutyrate will generally dissociate into a beta-hydroxybutyrate anion and hydronium ion (H)3O +. As a result, the beta-hydroxybutyrate molecule can exchange protons and cations with dissolved beta-hydroxybutyrate. For the purpose of defining the relative amounts of beta 1-hydroxybutyrate and beta 2-hydroxybutyrate in a beta 0-hydroxybutyrate mixed salt-acid composition, the dissociation of the beta-hydroxybutyrate molecule and the exchange of protons and cations should not be understood as altering the molar ratio of free beta-hydroxybutyrate relative to the beta-hydroxybutyrate anion from beta-hydroxybutyrate. The total amount of free beta-hydroxybutyrate molecules in solution is the sum of dissolved non-deprotonated beta-hydroxybutyrate molecules and the beta-hydroxybutyrate anions formed by deprotonation of the beta-hydroxybutyrate molecules.
In other words, the total molar equivalent of beta-hydroxybutyrate in solution (whether deprotonated or not) is understood to be the difference between (i) the sum of the molar equivalents of the non-deprotonated beta-hydroxybutyrate molecules in solution and the total molar equivalents of beta-hydroxybutyrate anions (from all sources) and (ii) the total molar equivalent of the cationic charge provided by the cation from the beta-hydroxybutyrate compound (which is equal to the total molar equivalents of beta-hydroxybutyrate anions provided by the beta-hydroxybutyrate). Alkali metal cations such as sodium and potassium, provide 1 mole of cationic charge per mole of metal cation. In another aspect, alkaline earth metal cations such as magnesium and calcium provide 2 moles of cationic charge per mole of metal cation. 1 mole of deprotonated β -hydroxybutyrate molecules provides 1 mole of anionic charge and 1 mole of cationic charge.
In view of the foregoing, the mole fraction of beta-hydroxybutyrate in solution relative to the total moles of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate mixed hydrochloride-acid composition in solution is [ (i) - (ii)/i ], and the mole fraction of beta-hydroxybutyrate molecules from beta-hydroxybutyrate in solution is [ (ii) ÷ (i) ]. The mole fraction of each was multiplied by 100 to give the percentage of each in solution.
For example, if 100 molar equivalents of the salt-acid composition mixed in beta-hydroxybutyrate in dry powder form comprises 5% free non-deprotonated beta-hydroxybutyrate and 95% beta-hydroxybutyrate on a molar basis, then essentially 5 molar equivalents of beta-hydroxybutyrate molecules and 95 molar equivalents of beta-hydroxybutyrate anion will be present. When there is sufficient water to dissolve the beta-hydroxybutyrate, and if a portion of the beta-hydroxybutyrate molecules are deprotonated, the molar equivalent of the non-deprotonated beta-hydroxybutyrate will be less than 5 and the molar equivalent of the beta-hydroxybutyrate anion will be greater than 95. The degree of deprotonation of β -hydroxybutyrate in solution is related to the pH of the solution.
Whether beta-hydroxybutyrate is the R-enantiomer or the S-enantiomer depends on the tetrahedral orientation of the hydroxyl (or oxy in the case of esters) group on the 3-carbon (beta-carbon) relative to the planar carboxyl group.
Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, in an endogenous form, can be used as a fuel source by the patient's body during conditions of low glucose levels in the subject or when the patient's body supplements the available form of beta-hydroxybutyrate. The beta-hydroxybutyrate is commonly referred to as the "ketone body".
As used herein, a "ketogenic composition" is formulated to increase ketone body levels in a subject, including inducing and/or maintaining an elevated ketone body state, e.g., ketosis, at a desired level in a subject to which it is administered.
As used herein, "subject" or "patient" refers to a member of the animal kingdom, including mammals, such as, but not limited to, humans and other primates; rodents, fish, reptiles and birds. The subject may be any animal in need of treatment, or prevention, or suspected of being in need of treatment, or prevention. Prevention means taking measures to prevent a possible occurrence, for example in the case of a determination of hyperglycemia or diabetes. "patient" and "subject" are used interchangeably herein.
The term "unit dose" refers to a dosage form configured to deliver a specific amount or dose of a composition or a component thereof. Exemplary dosage forms include, but are not limited to, tablets, capsules, powders, food products, food additives, beverages (e.g., flavored, vitamin fortified, or non-alcoholic), beverage additives (e.g., flavored, vitamin fortified, or non-alcoholic), confectionaries, inhalants (pickers), lozenges, food supplements, dietetically acceptable sprays (e.g., flavored oral sprays), injectables (e.g., non-alcoholic injectables), and suppositories. Such dosage forms may be configured to provide a complete unit dose or a portion thereof (e.g., a unit dose of 1/2, 1/3, or 1/4).
Another dosage form that may be used to provide a unit dose of a composition or a component thereof is a unit dose measurement device, such as a cup, spoon, syringe, dropper, spoon, spatula, or colonic lavage device, configured to hold therein a measured amount of the composition equal to a complete unit dose or a portion thereof (e.g., a unit dose of 1/2, 1/3, or 1/4). For example, a bulk container (bulk container), such as a carton (carton), box, can, jar, bag, pouch, bottle, pot or tub, containing a number of unit doses (e.g., 5 to 250 or 10 to 150 unit doses) of a composition may be provided to a user along with a unit dose measuring device configured to provide unit doses or portions thereof of the composition or components thereof.
A kit for providing a composition as disclosed herein in bulk form while providing a unit dose of the composition may comprise a bulk container holding a quantity of the composition therein and a unit dose measuring device configured to provide a unit dose of the composition or a component thereof or a portion thereof. One or more unit dose measuring devices may be placed inside the bulk container at the time of sale, connected to the outside of the bulk container, pre-packaged with the bulk container in a larger package, or provided by the seller or manufacturer for use with one or more bulk containers.
The kit may contain instructions regarding the size of the unit dose or portion thereof, as well as the manner and frequency of administration. The instructions may be provided on the bulk container, pre-packaged with the bulk container, placed on packaging material sold with the bulk container, or otherwise provided by the seller or manufacturer (e.g., on a website, mail, flyer, product literature, etc.). The instructions may include a reference to how to use the unit dose measurement device to properly deliver the unit dose or portion thereof. The instructions may additionally or alternatively include references to commonly used unit dose measuring devices, such as spoons, spatulas, cups, etc., that are not provided with the bulk container (e.g., in the event that the provided unit dose measuring device is lost or misplaced). In such cases, the end user may construct the kit following instructions provided on or with the bulk container or otherwise provided by the vendor regarding the product and how to properly deliver the unit doses of the composition or fractions thereof.
As used herein, "ketosis" refers to a subject having a blood ketone level in the range of about 0.5mmol/L to about 16mmol/L in the subject. Ketosis can improve mitochondrial function, reduce reactive oxygen species production, reduce inflammation and increase neurotrophic factor activity. As used herein, "ketone adaptation" refers to long-term nutritional ketosis (>1 week) to achieve persistent non-pathological "mild ketosis" or "therapeutic ketosis".
In some cases, "elevated ketone body levels" may not mean that the subject is in a "clinical ketosis" state, but still has an elevated supply of ketone for the production of energy and/or for performing other beneficial effects of ketone bodies. For example, a "ketone-adapted" subject may not necessarily have elevated serum levels of ketone bodies, but may be able to utilize available ketone bodies more rapidly than a subject that is not "ketone-adapted". In such cases, "elevated ketone body levels" can refer to the total amount and/or ratio of ketone bodies utilized by the subject, rather than plasma levels.
The term "short chain triglyceride" (SCT) refers to a molecule having a glycerol backbone linked to three medium chain fatty acids. Short chain fatty acids may be 2 to 5 carbon atoms in length. Exemplary short chain fatty acids are acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid. An exemplary SCT is tributyrin.
The term "medium chain triglycerides" (MCTs) refers to molecules having a glycerol backbone linked to three medium chain fatty acids. Medium chain fatty acids may be 6 to 12 carbon atoms in length, and more likely 8 to 10 carbon atoms in length. Exemplary fatty acids are caprylic acid (also known as octanoic acid), containing 8 carbon molecules, and capric acid (also known as capric acid), containing 10 carbon molecules. MCT, medium chain fatty acids and mono-and diglycerides are ketone body precursors that can provide an additional source for the production of ketone bodies independent of beta-hydroxybutyrate.
The term "long chain triglyceride" (LCT) refers to a molecule having a glycerol backbone linked to three medium chain fatty acids. The long chain fatty acids may be more than 12 carbon atoms in length.
The term "administering" or variations thereof is used herein to describe the process in which the disclosed compositions are delivered to a subject. The compositions can be administered in a variety of ways, including orally, intragastrically, and parenterally (meaning intravenous and intraarterial, and other suitable parenteral routes), and the like.
Non-racemic beta-hydroxybutyrate compositions
A composition for increasing ketone body levels (including promoting and/or maintaining ketosis) in a subject comprises a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate enriched with the R-enantiomer (i.e. greater than 50% and less than 100% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and less than 50% and greater than 0% S-beta-hydroxybutyrate on an enantiomeric equivalent basis).
In some embodiments, the non-racemic mixture of R- β -hydroxybutyrate and S- β -hydroxybutyrate comprises 50.5% to 99.5%, 51% to 99%, 52% to 98%, 53% to 97%, 55% to 95%, 55% to 89%, 57% to 87%, or 60% to 80% of the R- β -hydroxybutyrate enantiomer and 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- β -hydroxybutyrate enantiomer by enantiomeric equivalent.
The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more of the enantiomer of R-beta-hydroxybutyrate (the endogenous form produced by the mammal) than the enantiomer of S-beta-hydroxybutyrate, as compared to the racemic mixture, to provide a greater and/or faster ketogenic effect. Because the R- β -hydroxybutyrate enantiomer is endogenously produced by the mammal during ketosis, administration of the R- β -hydroxybutyrate enantiomer to a subject provides additional amounts and/or increased plasma levels that are immediately available to the body, for example, for energy production (e.g., as an alternative energy source to glucose), as compared to the racemic mixture of R, S- β -hydroxybutyrate (also known as DL- β -hydroxybutyrate). The presence of the S-enantiomer can modulate and extend this effect.
In contrast to conventional wisdom of minimizing or eliminating S-beta-hydroxybutyrate (which is not endogenously produced by mammals and is believed to be non-natural and potentially harmful), the non-racemic mixture comprises a significant amount of the S-beta-hydroxybutyrate enantiomer to produce one or more desired effects in mammals. For example, administration of S- β -hydroxybutyrate with R- β -hydroxybutyrate may result in at least one of: (1) increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; (2) endogenous transformation of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of S-beta-hydroxybutyrate to fatty acids and sterols; (4) prolongation of ketosis; (5) the metabolism of S-beta-hydroxybutyrate is independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate; (6) an increase in fetal development; (7) the growth years are increased; (8) reduced endogenous production of acetone during ketosis; (9) regulates the metabolism of R-beta-hydroxybutyrate and glucose through the signaling of S-beta-hydroxybutyrate; (10) antioxidant activity; and (11) production of acetyl-CoA.
The non-racemic mixture of R- β -hydroxybutyrate and S- β -hydroxybutyrate can be used, for example, to produce one or more desired effects in a subject, including but not limited to appetite suppression, weight loss, fat loss, decreased blood glucose levels, improved mental alertness, increased body energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.
The composition may comprise a nutritionally or pharmaceutically acceptable carrier.
The R-beta-hydroxybutyrate and S-beta-hydroxybutyrate may be provided in a variety of forms such as salts and/or esters, as well as a certain amount of the free acid. The enantiomeric equivalent percentage of each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is defined as the molar amount of R-beta-hydroxybutyrate or S-beta-hydroxybutyrate divided by the total combined molar amount of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. The amount of any salt-forming cations and/or ester-forming alcohols is excluded and is not taken into account in determining the enantiomeric equivalent percentages of each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. For example, the weight contribution of the cation, alcohol or complexing agent may be taken into account so as not to be decisive with respect to the enantiomeric equivalents of R-BHB and S-BHB.
In order not to overload the composition with R- β -hydroxybutyrate and a significant amount of the precursor that is readily converted to R- β -hydroxybutyrate (i.e. the monoester of R-1, 3-butanediol and R- β -hydroxybutyrate (i.e. (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester)), the non-racemic mixture of R- β -hydroxybutyrate and S- β -hydroxybutyrate will not contain more than 88%, or 87%, or 86%, or 85% by enantiomeric equivalent of the (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester.
In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is provided in a composition comprising a dietary or pharmaceutically acceptable carrier. Some examples include powders, liquids, tablets, capsules, food products, food additives, beverages, beverage additives, confectionaries, inhalants, lozenges, food supplements, sprays, injectables, and suppositories.
In some embodiments, the non-racemic mixture of R- β -hydroxybutyrate and S- β -hydroxybutyrate may be provided as a salt, for example one or more salts of an alkali metal, alkaline earth metal, transition metal, amino acid or amino acid metabolite. Some examples include lithium, sodium, potassium, magnesium, calcium, zinc, iron (e.g., iron II and/or iron III), chromium, manganese, cobalt, copper, molybdenum, selenium, arginine, lysine, leucine, isoleucine, histidine, ornithine, citrulline, glutamine, and sarcosinate.
The non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate may be provided as one or more esters, for example mono-, di-, tri-, oligo-and polyesters. Some examples include monoesters of ethanol, monoesters of 1-propanol, monoesters of 1, 2-propanediol, diesters of 1, 2-propanediol, monoesters of 1, 3-propanediol, diesters of 1, 3-propanediol, monoesters of S-, R-, or S-R-1, 3-butanediol, diesters of S-, R-, or S-R-1, 3-butanediol, monoglycerides, (3S) -hydroxybutyl (3S) -hydroxybutyrate monoester, (3R) -hydroxybutyl (3S) -hydroxybutyrate, monoglycerides, diglycerides, triglycerides, acetoacetates, dimers, trimers, oligomers, and polyesters comprising beta-hydroxybutyrate repeating units, as well as beta-hydroxybutyrate and one or more other hydroxy-carboxylic acids (e.g., lactic acid, and mixtures thereof, Citric acid, acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, and malic acid), and/or beta-hydroxybutyrate and/or complex oligomers or polymers of one or more diols (e.g. 1, 3-propanediol and 1, 3-butanediol), and one or more polyacids (e.g. tartaric acid, citric acid, malic acid, succinic acid, and fumaric acid). Although the (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester may be included, it should not exceed 88%, or 87%, or 86% or 85% by enantiomeric equivalent of the composition.
The non-racemic mixture may comprise one or more salts of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with relatively small amounts of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate in the acid form. The ratio of the salt form to the acid form of R-beta-hydroxybutyrate is not necessarily the same as the ratio of the salt form to the acid form of S-beta-hydroxybutyrate. This allows for more 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 greater than 0% free beta-hydroxybutyrate, e.g., up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97% of one or more R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate in molar equivalent, 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%, 1.8%, 2.25%, and less than 3% molar equivalent, 20%, 15%, 10%, 8%, 6%, 5%, 4% or 3% free R- β -hydroxybutyrate and/or free S- β -hydroxybutyrate.
In cases where a large amount of the R-enantiomer is contained relative to a non-racemic mixture of the S-enantiomer, a higher proportion of free S- β -hydroxybutyrate relative to S- β -hydroxybutyrate may be used and still obtain a composition with a neutral or other desired pH. That is, even though the relative amount of S- β -hydroxybutyrate is high relative to S- β -hydroxybutyrate, the total amount of acid can be relatively small if the amount of R- β -hydroxybutyrate is high.
In other embodiments, the non-racemic mixture may comprise one or more ester forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with relatively minor amounts of the acid forms of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate. In other embodiments, the non-racemic mixture may comprise both the salt and ester forms of R- β -hydroxybutyrate and S- β -hydroxybutyrate in combination with relatively minor amounts of the acid form of R- β -hydroxybutyrate and/or S- β -hydroxybutyrate.
In some embodiments, the composition may comprise at least one medium chain fatty acid, or a mono-, di-, or tri-glyceride of said at least one medium chain fatty acid, wherein the medium chain fatty acid has from 6 to 12 carbons, preferably from 8 to 10 carbons. The composition may comprise at least one short chain fatty acid, or a mono-, di-, or tri-glyceride of said at least one short chain fatty acid, wherein the short chain fatty acid has less than 6 carbons. Although less preferred, 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.
Some examples of short chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid. Some examples of medium chain fatty acids include caproic acid, caprylic acid, capric acid, and lauric acid. Some 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.
Some examples and sources of medium chain fatty acids or esters thereof, such as medium chain triglycerides, include coconut oil, coconut milk powder, fractionated coconut oil, palm kernel oil, caprylic acid, capric acid, isolated medium chain fatty acids (e.g., isolated caproic acid, isolated caprylic acid, isolated capric acid), medium chain triglycerides in purified or native form, such as coconut oil, and ester derivatives of medium chain fatty acid ethoxylated triglycerides, ketene triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives, and triglyceride derivatives, and salts of medium chain triglycerides. Ester derivatives optionally include alkyl ester derivatives such as methyl, ethyl, propyl, butyl, hexyl and the like.
Administration of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate results in elevated and sustained blood levels of ketone bodies, thereby taking advantage of the metabolic and physiological advantages of persistent ketosis. Increasing the levels of ketone bodies in the blood provides greater flexibility in dietary selection for the subject compared to methods aimed at inducing and maintaining ketosis based solely on diet (e.g., based on fasting and/or limited carbohydrate intake). For example, a subject who has been administered a non-racemic mixture of appropriate amounts of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate will be able to occasionally eat carbohydrates or sugar-based foods without compromising the ketogenic state and transitioning back to the glucose-based metabolic state. In addition, such administration facilitates easier transition to ketogenic state while reducing or eliminating the deleterious effects typically associated with entry ketosis.
In some embodiments, the ketogenic composition further comprises a therapeutically effective amount of vitamin D3. Vitamin D3Is believed to work with magnesium and calcium to promote good bone health and prevent undesirable calcification of soft tissue. In some preferred embodiments, vitamin D3Included in such amounts are: such that the average daily dose of the ketogenic composition comprises from about 200IU ("International Unit") to about 8000IU, or from about 400IU to about 4000IU, or from about 600IU to about 3000IU of vitamin D3. In some embodiments, vitamin D3Included in such amounts are: such that the average daily dose of the ketogenic composition comprises from about 5 μ g to about 200 μ g, or from about 10 μ g to about 100 μ g, or from about 15 μ g to about 75 μ g of vitamin D3。
Some embodiments further comprise one or more additional ketone precursors or extenders. These additional ketone precursors or supplements may comprise acetoacetic acid, ketone esters, and/or other compounds that result in elevated blood ketone levels without adding more electrolytes to the blood stream. Other additives include metabolites that enhance the action or transport of ketone bodies into mitochondria, caffeine, theobromine, and nootropic agents, such as L-alpha glycerophosphorylcholine ("alpha GPC").
The composition may include a flavoring agent that helps to mask the otherwise unpleasant taste of the beta-hydroxybutyrate compound. These include essential oils such as peppermint, natural and artificial sweeteners, and other flavoring agents known in the art.
In some embodiments, the ketogenic composition may further comprise one or more additional components configured to reduce the hygroscopicity of the composition. For example, various anti-caking agents, flow agents and/or moisture absorbing agents may be included in a type and amount that is safe for consumption. Such additional components may comprise one or more of the following: aluminosilicates, ferrocyanide, carbonates or bicarbonates, silicates (e.g., sodium or calcium silicate), silica, phosphates (e.g., dicalcium phosphate or tricalcium phosphate), talc, powdered cellulose, calcium carbonate, and the like.
Administration of
In some embodiments, the compositions disclosed herein may be used in a method for increasing ketone body levels (including promoting and/or maintaining ketosis) in a subject, the method comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of one or more of the compositions disclosed herein. Some examples of beneficial effects of increasing ketone body levels (including promoting and/or maintaining ketosis) in a subject include one or more of the following: appetite suppression, weight loss, fat loss, reduced blood glucose levels, improved mental alertness, increased body energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.
Administering a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the ratio or percentage of enantiomers disclosed herein provides one or more of the following: increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; endogenous transformation 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; prolongation of ketosis; the metabolism of S-beta-hydroxybutyrate is independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate; an increase in fetal development; the growth years are increased; reduced endogenous production of acetone during ketosis; regulates the metabolism of R-beta-hydroxybutyrate and glucose through the signaling of S-beta-hydroxybutyrate; antioxidant activity; and production of acetyl CoA.
The ketogenic compositions described herein can be administered to a subject at a therapeutically effective dose and/or frequency to induce or maintain ketosis. In some embodiments, a single dose will comprise the following amounts of a non-racemic mixture of R- β -hydroxybutyrate and S- β -hydroxybutyrate: from about 0.5 grams to about 25 grams, or from about 0.75 grams to about 20 grams, or from about 1 gram to about 15 grams, or from about 1.5 grams to about 12 grams.
In some embodiments, the ketogenic composition may comprise or be administered with other supplements (e.g., vitamin D3, vitamins, minerals, nootropic agents, and other supplements known in the art). Some examples of vitamins, minerals, and herbal supplements that can be added to the ketogenic composition include one or more of the following: vitamin A, vitamin C, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese, chromium, caffeine, theobromine, theophylline, methomorphine (methylliberine), huperzine A, epicatechin, and enzymes.
In some embodiments, the composition may further comprise one or more short chain fatty acids, medium chain fatty acids, long chain fatty acids, fatty acid esters, or monoglycerides, diglycerides, or triglycerides of short chain fatty acids, medium chain fatty acids, long chain fatty acids as compared to the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate alone to provide an additional source of ketone bodies as discussed herein for maintaining ketosis for a longer period of time. In some embodiments, the composition is preferably administered such that the ratio of the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to short chain fatty acids, medium chain fatty acids, long chain fatty acids (or esters thereof) is from about 4: 1 to about 1: 4, or from about 2: 1 to about 1: 2, or from about 1.5: 1 to about 1: 1.5.
In some embodiments, the subject preferably follows a ketogenic diet that limits carbohydrate and protein intake during administration of the composition. For example, a subject may limit dietary intake to a ratio of about 65% fat, about 25% protein, and about 10% carbohydrate. The resulting therapeutic ketosis provides rapid and sustained ketoadaptation as a metabolic treatment for a wide range of metabolic disorders and nutritional support for therapeutic fasting, weight loss and performance enhancement. Thus, the compositions are typically administered to a subject in whom promotion and/or maintenance of ketosis is desired once daily, twice daily, or three times daily.
In a preferred embodiment, the ketogenic composition may be administered orally in solid and/or powdered form, for example as a powdered mixture (e.g., a powder-filled gelatin capsule), a hard compressed tablet, or other oral route of administration known to those skilled in the art.
In some embodiments, multiple doses of the composition are administered over a period of time. The frequency of administration of the composition can vary depending on any of a variety of factors, such as the time of treatment from the start of the previous treatment, the purpose of the treatment, and the like. The duration of administration of the composition (e.g., the period of time during which the agent is administered) can vary depending on any of a variety of factors, including the subject's response, the desired therapeutic effect, and the like.
The amount of the composition to be administered may vary depending on factors such as: susceptibility of the individual, age, sex, and weight of the individual, idiosyncratic response (idiosyncratic response) of the individual, and the like. A "therapeutically effective amount" is that amount necessary to promote a therapeutically effective result (i.e., therapeutic ketosis) in vivo. In accordance with the present disclosure, a suitable single dose size is a dose that is capable of preventing or alleviating (reducing or eliminating) symptoms in a patient when administered one or more times over a suitable period of time.
The amount of the composition administered will depend on the potency, absorption, distribution, metabolism, and excretion rate of the unused ketone bodies, electrolytes, the method of administration and the particular condition being treated, as well as other factors known to those skilled in the art. The dosage should be sufficient to affect the desired response, e.g., a therapeutic or prophylactic response to a particular disorder or condition, taking into account the severity of the condition to be alleviated. The compounds may be administered once, or may be administered separately and at intervals. It is understood that administration can be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.
Example IV
The following is a description of exemplary non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate compositions and other ketogenic compositions that can be used to increase ketone levels in a subject, including inducing and/or maintaining the ketogenic state in a subject administered thereto. It is to be understood that the beta-hydroxybutyrate compounds described in the examples can be in the form of salts, esters, dimers, trimers, oligomers and polymers as discussed herein. From the standpoint of the examples, an important matter is the enantiomeric percentage or ratio of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate.
In some cases, the composition may be a blend of beta-hydroxybutyrate, a blend of beta-hydroxybutyrate and esters, a blend of beta-hydroxybutyrate and free beta-hydroxybutyrate, or a blend of beta-hydroxybutyrate, and free beta-hydroxybutyrate to provide a desired electrolyte balance, taste, and/or pharmacokinetic response. The compositions may also be combined with short, medium or long chain fatty acids, esters, glycerides and other supplements disclosed herein to provide desired levels of elevated ketone bodies and other effects.
Example 1
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 51% enantiomer of R-beta-hydroxybutyrate by enantiomeric equivalent and 49% enantiomer of S-beta-hydroxybutyrate by enantiomeric equivalent. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture. In another aspect, inclusion of the S- β -hydroxybutyrate enantiomer provides a longer ketosis status and/or other benefits as disclosed herein.
The non-racemic mixture is readily administered as a ketogenic composition, for example in powder form as a dietary supplement to be mixed with food or drink, in the form of one or more capsules or tablets, or in liquid form, for example an oral spray.
Example 2
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 52% enantiomer equivalents of R-beta-hydroxybutyrate and 48% enantiomer equivalents of S-beta-hydroxybutyrate. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture. In another aspect, inclusion of the S- β -hydroxybutyrate enantiomer provides a longer ketosis status and/or other benefits as disclosed herein.
Example 3
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 53% enantiomer equivalent of R-beta-hydroxybutyrate and 47% enantiomer equivalent of S-beta-hydroxybutyrate. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture. In another aspect, inclusion of the S- β -hydroxybutyrate enantiomer provides a longer ketosis status and/or other benefits as disclosed herein.
Example 4
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 55% R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 45% S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture. In another aspect, inclusion of the S- β -hydroxybutyrate enantiomer provides a longer ketosis status and/or other benefits as disclosed herein.
Example 5
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 57% R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 43% S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 4. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 6
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 59% by enantiomeric equivalent of the R-beta-hydroxybutyrate enantiomer and 41% by enantiomeric equivalent of the S-beta-hydroxybutyrate enantiomer. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 5. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 7
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 65% by enantiomeric equivalent of the R-beta-hydroxybutyrate enantiomer and 35% by enantiomeric equivalent of the S-beta-hydroxybutyrate enantiomer. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 6. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 8
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 70% R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 30% S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 7. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 9
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 75% enantiomer equivalents of R-beta-hydroxybutyrate and 25% enantiomer equivalents of S-beta-hydroxybutyrate. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 8. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 10
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 80% R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 20% S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 9. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 11
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 85% R-beta-hydroxybutyrate enantiomer by enantiomeric equivalent and 15% S-beta-hydroxybutyrate enantiomer by enantiomeric equivalent. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 10. In another aspect, the inclusion of the enantiomer of S-beta-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R-beta-hydroxybutyrate on an enantiomeric equivalent basis.
Example 12
A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 89% by enantiomeric equivalent of the R-beta-hydroxybutyrate enantiomer and 11% by enantiomeric equivalent of the S-beta-hydroxybutyrate enantiomer. Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 11. In another aspect, the inclusion of the enantiomer of S-B-hydroxybutyrate provides a longer ketosis status and/or other benefits as disclosed herein compared to compositions comprising 90% to 100% enantiomer of R- β -hydroxybutyrate on an enantiomeric equivalent basis.
Example 13
The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with the racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 99.5% by enantiomeric equivalent of the R-beta-hydroxybutyrate enantiomer and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0.5% by enantiomeric equivalent of the S-beta-hydroxybutyrate enantiomer, with the proviso that the non-racemic mixture does not comprise greater than 88%, or 87%, or 86%, or 85% by enantiomeric equivalent of the (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester (i.e. R- Monoesters of 1, 3-butanediol and R- β -hydroxybutyrate). Because the non-racemic mixture contains more R- β -hydroxybutyrate enantiomer, the onset of ketosis for a given dose is accelerated compared to the same dose of the racemic mixture or the non-racemic mixtures of examples 1 to 12.
Example 14
Any of the preceding embodiments are modified by combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with a dietary or pharmaceutically acceptable carrier.
Example 15
Any of the preceding embodiments are modified by combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more medium chain triglycerides and/or one or more mono-or diglycerides of one or more medium chain fatty acids and/or medium chain fatty acids.
Example 16
Any of the foregoing embodiments are modified by combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more short chain triglycerides and/or one or more short chain fatty acids and/or one or more mono-or diglycerides of short chain fatty acids.
Example 17
Any of the foregoing embodiments are modified by combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more long chain triglycerides and/or one or more long chain fatty acids and/or one or more mono-or diglycerides of long chain fatty acids.
Example 18
By combining a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more supplements (e.g. vitamin D)3Vitamins, minerals, and other supplements known in the art) to modify any of the foregoing embodiments.
Example 19
Any of the preceding embodiments is modified by including one or more salts of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-hydroxybutyrate or S-beta-hydroxybutyrate to provide a mixture of R-and S-beta-hydroxybutyrate and free R-and/or S-beta-hydroxybutyrate, wherein the mixture includes less than 100% of the one or more beta-hydroxybutyrate and greater than 0% free beta-hydroxybutyrate including up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97% by molar equivalent of the one or more salts of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate, and at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75% or 3% by molar equivalent of free R- β -hydroxybutyrate and/or free S- β -hydroxybutyrate.
Example 20
Any of the preceding embodiments is modified by including one or more esters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-hydroxybutyrate or S-beta-hydroxybutyrate to provide a mixture of R-and S-beta-hydroxybutyrate forms and free R-and/or S-beta-hydroxybutyrate, wherein the non-racemic mixture comprises less than 100% one or more beta-hydroxybutyrate and greater 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 to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
Claims (20)
1. A composition for administering ketone bodies to a subject, comprising:
a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprising greater than 50% and less than 100% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and less than 50% and greater than 0% S-beta-hydroxybutyrate on an enantiomeric equivalent basis, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprises:
at least one salt of R-beta-hydroxybutyrate;
at least one salt of S-beta-hydroxybutyrate; and
at least one of R-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid, and
wherein the composition is a powder.
2. The composition of claim 1, wherein the non-racemic mixture comprises 50.5% to 99.5% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and 49.5% to 0.5% S-beta-hydroxybutyrate on an enantiomeric equivalent basis.
3. The composition of claim 1 or 2, wherein the non-racemic mixture comprises 51% to 99% R- β -hydroxybutyrate on an enantiomeric equivalent basis and 49% to 1% S- β -hydroxybutyrate on an enantiomeric equivalent basis.
4. The composition of any one of claims 1 to 3, wherein the non-racemic mixture comprises 52% to 98% R-beta-hydroxybutyrate in enantiomeric equivalents and 48% to 2% S-beta-hydroxybutyrate in enantiomeric equivalents.
5. The composition of any one of claims 1 to 4, wherein the non-racemic mixture comprises 53% to 97% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and 47% to 3% S-beta-hydroxybutyrate on an enantiomeric equivalent basis.
6. The composition of any one of claims 1 to 5, wherein the non-racemic mixture comprises 90% to 99.9% R-beta-hydroxybutyrate and S-beta-hydroxybutyrate combined in molar equivalents and 10% to 0.1% R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate in molar equivalents.
7. The composition of any one of claims 1 to 6, wherein the non-racemic mixture comprises 94% to 99.5% by molar equivalents of the combined R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and 6% to 0.5% by molar equivalents of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate.
8. The composition of any one of claims 1 to 7, wherein the non-racemic mixture comprises 96% to 99% R-beta-hydroxybutyrate and S-beta-hydroxybutyrate combined in molar equivalents and 4% to 1% R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate in molar equivalents.
9. The composition of any one of claims 1 to 8, wherein 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.
10. The composition of any one of claims 1 to 9, further comprising at least one short chain fatty acid having less than 6 carbons, or a monoglyceride, diglyceride, or triglyceride of the at least one short chain fatty acid.
11. The composition of any one of claims 1 to 10, further comprising at least one supplement selected from the group consisting of: vitamins, minerals, nootropic drugs and herbal supplements.
12. A composition for administering ketone bodies to a subject, comprising:
a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprising greater than 50% and less than 100% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and less than 50% and greater than 0% S-beta-hydroxybutyrate on an enantiomeric equivalent basis, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprises:
at least one R-beta-hydroxybutyrate;
at least one S-beta-hydroxybutyrate; and
at least one of R-beta-hydroxybutyric acid or S-beta-hydroxybutyric acid, and
wherein the composition is provided as or in a tablet, capsule, powder, food product, food additive, flavored beverage, vitamin-fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin-fortified beverage additive, non-alcoholic beverage additive, candy, inhalant, lozenge, food supplement, flavored mouth spray, or suppository.
13. The composition of claim 12, wherein the non-racemic mixture comprises 50.5% to 99.5% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and 49.5% to 0.5% S-beta-hydroxybutyrate on an enantiomeric equivalent basis.
14. The composition of claim 12 or 13, wherein the non-racemic mixture comprises 94% to 99.5% R- β -hydroxybutyrate and S- β -hydroxybutyrate combined in molar equivalents and 6% to 0.5% R- β -hydroxybutyrate and/or S- β -hydroxybutyrate in molar equivalents.
15. The composition of any one of claims 12 to 14, wherein 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, and wherein the composition is a powder.
16. The composition of any one of claims 12 to 15, further comprising at least one supplement selected from the group consisting of: vitamins, minerals, nootropic drugs and herbal supplements.
17. A composition for administering ketone bodies to a subject, comprising:
a dietary or pharmaceutically acceptable carrier selected from: tablets, capsules, powders, food products, food additives, flavored drinks, vitamin-fortified beverages, non-alcoholic beverages, flavored drink additives, vitamin-fortified beverage additives, non-alcoholic beverage additives, candies, inhalants, lozenges, food supplements, flavored oral sprays and suppositories; and
a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprising greater than 50% and less than 100% R-beta-hydroxybutyrate on an enantiomeric equivalent basis and less than 50% and greater than 0% S-beta-hydroxybutyrate on an enantiomeric equivalent basis, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate comprises:
at least one R-beta-hydroxybutyrate or R-beta-hydroxybutyrate;
at least one S-beta-hydroxybutyrate or S-beta-hydroxybutyrate; and
at least one of R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.
18. A kit for administering ketone bodies to a subject, comprising:
the composition of any one of claims 1 to 17;
a container having the composition disposed therein; and
a measurement device configured to hold a unit dose of the composition, or a portion thereof, therein, wherein the unit dose of the composition comprises from about 0.5g to about 25g of the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate.
19. The kit of claim 18, wherein the container is selected from the group consisting of: cartons, boxes, cans, jars, bags, pouches, bottles, kettles, and pails.
20. The kit of claim 18 or 19, wherein the measurement device is selected from the group consisting of: cups, spoons, syringes, droppers, spatulas, spoons, and colonic lavage devices.
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US16/272,165 US10596129B2 (en) | 2017-11-22 | 2019-02-11 | Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use |
US16/272,165 | 2019-02-11 | ||
US16/409,501 US10596131B2 (en) | 2017-11-22 | 2019-05-10 | Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use |
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US16/783,844 | 2020-02-06 | ||
US16/783,844 US11103470B2 (en) | 2017-11-22 | 2020-02-06 | Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use |
PCT/US2020/017555 WO2020167692A1 (en) | 2019-02-11 | 2020-02-10 | Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the r-enantiomer and methods of use |
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