WO2020167692A1 - Composés bêta-hydroxybutyrate non racémiques et compositions enrichies avec l'énantiomère r, et leurs méthodes d'utilisation - Google Patents

Composés bêta-hydroxybutyrate non racémiques et compositions enrichies avec l'énantiomère r, et leurs méthodes d'utilisation Download PDF

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WO2020167692A1
WO2020167692A1 PCT/US2020/017555 US2020017555W WO2020167692A1 WO 2020167692 A1 WO2020167692 A1 WO 2020167692A1 US 2020017555 W US2020017555 W US 2020017555W WO 2020167692 A1 WO2020167692 A1 WO 2020167692A1
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beta
hydroxybutyrate
composition
racemic mixture
equivalents
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PCT/US2020/017555
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English (en)
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Gary MILLET
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Access Global Sciences, Llc
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Priority claimed from US16/272,165 external-priority patent/US10596129B2/en
Priority claimed from US16/409,501 external-priority patent/US10596131B2/en
Priority claimed from US16/783,844 external-priority patent/US11103470B2/en
Application filed by Access Global Sciences, Llc filed Critical Access Global Sciences, Llc
Priority to CN202080013807.2A priority Critical patent/CN114025752A/zh
Priority to AU2020222897A priority patent/AU2020222897A1/en
Priority to EP20755289.4A priority patent/EP3923924A4/fr
Priority to JP2021546765A priority patent/JP2022520203A/ja
Priority to CA3129587A priority patent/CA3129587A1/fr
Publication of WO2020167692A1 publication Critical patent/WO2020167692A1/fr
Priority to JP2023171560A priority patent/JP2023166026A/ja

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • Ketone bodies can be used by cells of the body as a fuel to satisfy the body's energy needs, including the brain and heart.
  • blood ketone levels can increase to 2-3 mmol/L or more.
  • ketone bodies e.g, beta-hydroxybutyrate and acetoacetate
  • ketosis Upon transitioning into ketosis, or in other words, during ketogenic metabolism in the liver, the body uses dietary and bodily fats as a primary energy source. Consequently, once in ketosis, one can induce loss of body fat by controlling dietary fat intake and maintaining low carbohydrate intake and blood level to sustain ketosis.
  • ketosis the body is in ketogenesis and essentially burning fat for its primary fuel.
  • the body cleaves fats into fatty acids and glycerol and transforms fatty acids into acetyl CoA molecules, which are then eventually transformed through ketogenesis into the water-soluble ketone bodies beta-hydroxybutyrate (i.e., “b- hydroxybutyrate” or“BHB”), acetoacetate (also known as acetylacetonate), and acetone in the liver.
  • beta-hydroxybutyrate and acetoacetate are the primary ketone bodies used by the body for energy while acetone is removed and expelled as a by-product of ketogenesis.
  • ketone bodies The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle sparing properties, and improved cognitive and physical performance.
  • Science-based improvements in efficiency of cellular metabolism, managed through ketone supplementation, can beneficially impact physical, cognitive health, and psychological health, and have a long-term impact on health with respect to common avoidable diseases such as obesity, cardiovascular disease, neurodegenerative diseases, diabetes, and cancer.
  • ketosis is often accompanied by hypoglycemia, which can cause lethargy and light-headedness in many, resulting in an uncomfortable physiological and mental state commonly referred to as the“low-carb flu.”
  • hypoglycemia can cause lethargy and light-headedness in many, resulting in an uncomfortable physiological and mental state commonly referred to as the“low-carb flu.”
  • many people experience a down regulation in their metabolism as the body naturally goes into an“energy-saving” mode.
  • ketosis If a subject is successful in establishing ketosis, the act of sustaining ketosis is likewise difficult, if not more difficult, due to the need to maintain a rigid dietary ratio of carbohydrates and protein to fats. It is further complicated by the disruption of normal electrolyte balances that often occurs when transitioning into and maintaining a ketogenic state. The depletion and lowering of glycogen stores in the liver and muscles lessens the ability of the body to retain water, leading to more frequent urination, and accordingly, a greater loss of electrolytes. Further, the drop in insulin levels caused by ketosis effects the rate at which certain electrolytes are extracted by the kidneys, additionally lowering electrolyte levels in the body.
  • Negative effects of electrolyte imbalance include muscle aches, spasms, twitches and weakness, restlessness, anxiety, frequent headaches, feeling very thirsty, insomnia, fever, heart palpitations or irregular heartbeats, digestive issues such as cramps, constipation or diarrhea, confusion and trouble concentrating, bone disorders, joint pain, blood pressure changes, changes in appetite or body weight, fatigue (including chronic fatigue syndrome), numbness in joints, and dizziness, especially when standing up suddenly.
  • compositions used to promote ketosis in a mammal include 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 the endogenous form of beta- hydroxybutyrate, or R-beta-hydroxybutyrate, while Lowery et al. discourage use of the non-endogenous enantiomer, or S-beta-hydroxybutyrate.
  • Others such as those disclosed in U.S. Patent No.
  • Example compositions include a non-racemic mixture of R-beta-hydroxybutyrate and S- beta-hydroxybutyrate, wherein the non-racemic mixture is enriched with the R-beta- hydroxybutyrate enantiomer relative to the S-beta-hydroxybutyrate enantiomer, such as 50.5% to 99.5% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 49.5% to 0.5% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrate enantiomer (i.e., more than 50% and less than 100%), the endogenous form produced by a mammal, than the S-beta- hydroxybutyrate enantiomer (i.e., less than 50% and more than 0%) in order to provide a greater and/or faster ketogenic effect compared to a racemic mixture.
  • administering the R-beta-hydroxybutyrate enantiomer to a subject provides an additional quantity and/or increased blood plasma level that can be immediately utilized by the body, such as for producing energy (e.g , as an alternative energy source to glucose).
  • the non-racemic mixture contains a significant quantity of the S-beta-hydroxybutyrate enantiomer in order to produce one or more desired effects in the mammal, as discussed herein.
  • non-racemic mixtures enriched with R-beta-hydroxybutyrate relative to S-beta-hydroxybutyrate can include the free acid form of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate.
  • a non-racemic mixture may contain one or more salts or esters of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with R-beta-hydroxybutyric acid, and optionally S-beta-hydroxybutyric acid.
  • beta-hydroxybutyric acid with one or more beta-hydroxybutyrate salts is beneficial because it reduces electrolyte load, increases absorption rate, improves taste, facilitates easier formulation, and reduces the need to add citric acid or other edible acids to obtain a composition having neutral or acidic pH.
  • compositions disclosed herein can be used in a method for increasing ketone body level in a subject, including promoting and/or sustaining 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.
  • beneficial effects of increased ketone body level in a subject include one or more of appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental alertness, increased physical energy, improved cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes, improvement of neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, anti- glycation, reduction in epileptic seizer, improved mood, increased strength, increased muscle mass, or improved body composition.
  • administering the non-racemic mixture of R-beta- hydroxybutyrate and S-beta-hydroxybutyrate in enantiomeric ratios or percentages disclosed herein provides one or more of: increased endogenous production of R-beta- hydroxybutyrate and acetoacetate; endogenous conversion of the S-beta-hydroxybutyrate into one or both of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of the S-beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis; metabolism of the S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate; increased fetal development; increased growth years; reduced endogenous production of acetone during ketosis; signaling by the S-beta-hydroxybutyrate that modulates metabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity; and production of acety
  • composition may include a nutritionally or pharmaceutically acceptable carrier.
  • the compound“beta-hydroxybutyrate,” also known as b-hydroxybutyrate, 3- hydroxybutyrate, bHB, or BHB, is the deprotonated form of beta-hydroxybutyric acid, which is a hydroxycarboxybc acid having the general formula CH 3 CH 2 OHCH 2 COOH.
  • the deprotonated form present at typical biological pH levels is CH 3 CH 2 OHCH 2 COO .
  • the general chemical structure shown below represents beta-hydroxybutyrate compounds that may be utilized in the disclosed compositions:
  • X can be hydrogen, metal ion, amino cation such as from an amino acid, alkyl, alkenyl, aryl, or acyl.
  • the compound When X is a hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compounds is a beta-hydroxybutyrate salt. When X is alkyl, alkenyl, aryl, or acyl, the compounds is a beta-hydroxybutyrate ester.
  • the foregoing compounds can be in any desired physical form, such as crystalline, powder, solid, liquid, solution, suspension, or gel.
  • salt does not mean or imply any particular physical state, such as a crystalline, powder, other solid form, dissolved in water to form a liquid solution, dispersed in a liquid to form a suspension, or gel.
  • a salt can be formed in solution, such as by at least partially neutralizing beta-hydroxybutyric acid with a strong or weak base, such as an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate, basic amino acid, and the like.
  • the composition can include a mixture of one or more beta- hydroxybutyrate salts and beta-hydroxybutyric acid(s).
  • Providing R-beta- hydroxybutyrate in its acid form can be beneficial because of its much quicker absorption response time compared to the salt form. Nonetheless, even though the acid form by itself is a liquid with extremely low pH and unpalatable taste, when made or combined with the salt form(s) and where the amount of beta-hydroxybutyric acid is small relative to the salt form(s), the composition can still form a solid, powder or other form typical of the salt form(s). In such case, the combined salt and acid form of BHB has acceptable pH and taste.
  • BHB compositions that include both salt and acid forms have advantages, such as increased absorption rate, increased bioavailability, lower electrolyte load, ease of manufacture, significantly improved taste, and reduced need for citric acid or other edible acids to obtain a composition with neutral or acidic pH. It will be appreciated that beneficial effects can also be provided using a mixture of BHB salt(s) and/or ester(s) and the acid form(s) of BHB.
  • beta-hydroxybutyric acid means the sum of non-deprotonated and deprotonated beta-hydroxybutyric acid molecules.
  • a deprotonated beta- hydroxybutyric acid molecule generally means a molecule that has released a proton to form a hydronium ion (H3O+) and a beta-hydroxybutyrate anion (e.g., dissolved in water).
  • Free beta-hydroxybutyric acid molecules are typically not deprotonated to any significant degree when contained in a beta-hydroxybutyrate mixed salt-acid composition in dry powder or other solid form.
  • the fractional amount of free beta-hydroxybutyric acid in a beta-hydroxybutyrate mixed salt-acid composition on a weight basis is the weight of free beta-hydroxybutyric acid divided by the combined weight of free beta-hydroxybutyric acid and beta-hydroxybutyrate salt(s).
  • the fractional amount of free beta-hydroxybutyric acid in an beta-hydroxybutyrate mixed salt-acid composition are the molar equivalents of free beta-hydroxybutyric acid divided by the sum of molar equivalents of free beta-hydroxybutyric acid and beta- hydroxybutyrate anions provided by the beta-hydroxybutyrate salt(s).
  • a portion of the beta-hydroxybutyric acid When dissolved in water, a portion of the beta-hydroxybutyric acid will typically dissociate into beta-hydroxybutyrate anions and hydronium ions (H3O+). As a result, beta-hydroxybutyric acid molecules can exchange protons and cations with dissolved beta-hydroxybutyrate salts.
  • beta-hydroxybutyric acid and beta-hydroxybutyrate salt(s) in a beta-hydroxybutyrate mixed salt-acid composition dissociation of beta-hydroxybutyric acid molecules and the exchange of protons and cations is not understood as changing the molar ratio of free beta-hydroxybutyric acid relative to beta-hydroxybutyrate anions from the beta- hydroxybutyrate salt(s).
  • the total quantity of free beta-hydroxybutyric acid molecules in solution is the sum of dissolved beta-hydroxybutyric acid molecules that are not deprotonated and beta-hydroxybutyrate anions formed by deprotonation of beta- hydroxybutyric acid molecules.
  • the total molar equivalents of beta-hydroxybutyric acid in solution is understood to be the difference between (i) the sum of molar equivalents of non-deprotonated beta-hydroxybutyric acid molecules and total molar equivalents of beta-hydroxybutyrate anions in solution (from all sources) and (ii) the total molar equivalents of cationic charge provided by cations from the beta- hydroxybutyrate salt compounds (which equals the total molar equivalents of beta- hydroxybutyrate anions provided by the beta-hydroxybutyrate salt(s)).
  • Alkali metal cations such as sodium and potassium provide 1 mole of cationic charge per mole of metal cations.
  • Alkaline earth metal cations such as magnesium and calcium, on the other hand, provide 2 moles of cationic charge per mole of metal cations.
  • 1 mole of deprotonated beta-hydroxybutyric acid molecules provide 1 mole of anionic charge and one mole of cationic charge.
  • the molar fraction of beta-hydroxybutyric acid in solution in relation to total moles of beta-hydroxybutyrate molecules from the beta- hydroxybutyrate mixed salt-acid composition in solution is [(i)-(ii) ⁇ (i)]
  • the molar fraction of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate salt(s)) in solution is [(ii) ⁇ (i)]. Multiplying the molar fraction of each by 100 gives the percentage of each in solution.
  • beta-hydroxybutyrate mixed salt- acid composition in dry powder form contained 5% of free non-deprotonated beta- hydroxybutyric acid and 95% beta-hydroxybutyrate salt(s) on a molar basis, there would be essentially 5 molar equivalents of beta-hydroxybutyric acid molecules and 95 molar equivalents of beta-hydroxybutyrate anions.
  • beta-hydroxybutyrate salt(s) When there is sufficient water to dissolve the beta-hydroxybutyrate salt(s), and if a portion of the beta-hydroxybutyric acid molecules were deprotonated, the molar equivalents of non-deprotonated beta- hydroxybutyric acid would be less than 5, and the molar equivalents of beta- hydroxybutyrate anions would be greater than 95.
  • the extent of deprotonation of beta- hydroxybutyric acid in solution is related to solution pH.
  • beta-hydroxybutyrate is the R- or S-enantiomer depends on the tetrahedral orientation of the hydroxy (or oxy group in the case of an ester) on the 3- carbon (beta-carbon) in relationship to the planar carboxyl group.
  • Beta-hydroxybutyrate typically R-beta-hydroxybutyrate, which is the endogenous form, can be utilized by a patient's body as a fuel source during instances of low glucose levels in the subject or when a patient’s body is supplemented with a usable form of beta-hydroxybutyrate.
  • Beta-hydroxybutyrate is commonly referred to as a “ketone body”.
  • a“ketogenic composition” is formulated to increase ketone body level in a subject, including 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.
  • “subject” or“patient” refers to members 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 requiring therapy, treatment, or prophylaxis, or any animal suspected of requiring therapy, treatment, or prophylaxis.
  • Prophylaxis means that regiment is undertaken to prevent a possible occurrence, such as where a high glucose or diabetes is identified.
  • “Patient” and “subject” are used interchangeably herein.
  • unit dose refers to a dosage form that is configured to deliver a specified quantity or dose of composition or component thereof.
  • Example dosage forms include, but are not limited to, tablets, capsules, powders, food products, food additives, beverages (such as flavored, vitamin fortified, or non-alcoholic), beverage additives (such as flavored, vitamin fortified, or non-alcoholic), candies, suckers, pastilles, food supplements, dietetically acceptable sprays (such as flavored mouth spray), injectables (such as an alcohol -free injectable), and suppositories.
  • Such dosage forms may be configured to provide a full unit dose or fraction thereof (e.g., 1/2, 1/3, or 1/4 of a unit dose).
  • a unit dose measuring device such as a cup, scoop, syringe, dropper, spoon, spatula, or colonic irrigation device, which is configured to hold therein a measured quantity of composition equaling a full unit dose or fraction thereof (e.g., 1/2, 1/3, or 1/4 of a unit dose).
  • a bulk container such as a carton, box, can, jar, bag, pouch, bottle, jug, or keg, containing several unit doses of composition (e.g., 5- 250 or 10-150 unit doses) can be provided to a user together with a unit dose measuring device that is configured to provide a unit dose, or fraction thereof, of composition or component thereof.
  • a unit dose measuring device that is configured to provide a unit dose, or fraction thereof, of composition or component thereof.
  • a kit for use in providing a composition as disclosed herein in bulk form, while providing unit doses of the composition may comprise a bulk container holding therein a quantity of composition and a unit dose measuring device configured to provide a unit dose, or fraction thereof, of composition or component thereof.
  • One or more unit dose measuring devices may be positioned inside the bulk container at the time of sale, attached to the outside of the bulk container, prepackaged with the bulk container within a larger package, or provided by the seller or manufacture for use with one or multiple bulk containers.
  • the kit may include instructions regarding the size of the unit dose, or fraction thereof, and the manner and frequency of administration.
  • the instructions may be provided on the bulk container, prepackaged with the bulk container, placed on packaging material sold with the bulk container, or otherwise provided by the seller or manufacturer (e.g., on websites, mailers, flyers, product literature, etc.)
  • the instructions may include a reference on how to use the unit dose measuring device to properly deliver a unit dose or fraction thereof.
  • the instructions may additionally or alternatively include a reference to common unit dose measuring devices, such as spoons, spatulas, cups, and the like, not provided with the bulk container (e.g., in case the provided unit dose measuring device is lost or misplaced).
  • a kit may be constructed by the end user when following instructions provided on or with the bulk container, or otherwise provided by the seller regarding the product and how to properly deliver a unit dose of composition, or fraction thereof.
  • Ketosis refers to a subject having blood ketone levels within the range of about 0.5 mmol/L and about 16 mmol/L in a subject. Ketosis may improve mitochondrial function, decrease reactive oxygen species production, reduce inflammation and increase the activity of neurotrophic factors.“Keto-adaptation” as used herein refers to prolonged nutritional ketosis (>1 week) to achieve a sustained nonpathological“mild ketosis” or“therapeutic ketosis.”
  • “elevated ketone body level” may not mean that a subject is in a state of “clinical ketosis” but nevertheless has an elevated supply of ketones for producing energy and/or for carrying out other beneficial effects of ketone bodies.
  • a subject that is“ketone adapted” may not necessarily have elevated blood serum levels of ketone bodies but rather is able to utilize available ketone bodies more rapidly compared to a subject that is not“ketone adapted.”
  • “elevated ketone body level” can refer to the total quantity and/or rate of ketone bodies being utilized by the subject rather than blood plasma levels.
  • SCT short chain triglycerides
  • exemplary short chain fatty acids are acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid.
  • An example SCT is tributyrin.
  • MCT medium chain triglycerides
  • MCTs refers to molecules having a glycerol backbone atached to three medium chain fatty acids.
  • Medium chain fatty acids can range from 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, comprising 8 carbon molecules, and capric acid, also known as decanoic acid, comprising 10 carbon molecules.
  • MCTs, medium chain fatty acids, and mono- and di-glycerides are ketone body precursors that can provide an additional source for the production of ketone bodies independent of beta-hydroxybutyrate.
  • LCT long chain triglycerides
  • compositions are delivered to a subject.
  • the composition may be administered in various ways including oral, intragastric, and parenteral (referring to intravenous and intra-arterial and other appropriate parenteral routes), among others.
  • compositions for increasing ketone body level in a subject comprise a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate enriched with the R- enantiomer (i.e., more than 50% and less than 100% by enantiomeric equivalents of R-beta-hydroxybutyrate and less than 50% and more than 0% by enantiomeric equivalents of S-beta-hydroxybutyrate).
  • the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains 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% by enantiomeric equivalents of the R-beta-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% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrate enantiomer, the endogenous form produced by a mammal, than the S-beta-hydroxybutyrate enantiomer in order to provide a greater and/or faster ketogenic effect compared to a racemic mixture. Because the R-beta- hydroxybutyrate enantiomer is endogenously produced by a mammal during ketosis, administering the R-beta-hydroxybutyrate enantiomer to a subject provides an additional quantity and/or increased blood plasma level that can be immediately utilized by the body, such as for producing energy (e.g.
  • S-beta-hydroxybutyrate aka DL-beta- hydroxybutyrate
  • the non-racemic mixture contains a significant quantity of the S-beta-hydroxybutyrate enantiomer in order to produce one or more desired effects in the mammal.
  • administering S-beta-hydroxybutyrate along with R-beta-hydroxybutyrate can result in at least one of: (1) increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; (2) endogenous conversion of the S-beta-hydroxybutyrate into one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of the S-beta-hydroxybutyrate into fatty acids and sterols; (4) prolonged ketosis; (5) metabolism of the S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate; (6) increased fetal development; (7) increased growth years; (8) reduced endogenous production of acetone during ketosis; (9) signaling by the S-beta-hydroxybutyrate that modulates metabolism of R-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11) production of acetyl-CoA.
  • the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be used, for example, to produce one or more desired effects in the subject, including but not limited to, appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental alertness, increased physical energy, improved cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes, improvement of neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, antiglycation, reduction in epileptic seizer, improved mood, increased strength, increased muscle mass, or improved body composition.
  • composition may include a nutritionally or pharmaceutically acceptable carrier.
  • the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be provided in various forms, such as salts and/or esters, together with a quantity of free acid form(s).
  • the percent enantiomer equivalents for each of R-beta-hydroxybutyrate and S-beta- hydroxybutyrate is defined by the molar quantity of either R-beta-hydroxybutyrate or S- beta-hydroxybutyrate divided by the total combined molar quantities of R-beta- hydroxybutyrate and S-beta-hydroxybutyrate.
  • any cations forming salts and/or alcohols forming esters are excluded and do not count in determining the percent enantiomeric equivalents for each of R-beta-hydroxybutyrate and S-beta- hydroxybutyrate.
  • the weight contributions of cations, alcohols, or complexing agents can be factored in so as to not tip the scale relative to enantiomeric equivalents of R-BHB and S-BHB.
  • the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate shall not contain more than 88%, or 87%, or 86%, or 85% by enantiomeric equivalents of (3R)-hydroxybutyl (3R)-hydroxybutyrate mono-ester.
  • 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.
  • a dietetically or pharmaceutically acceptable carrier examples include powders, liquids, tablets, capsules, food products, food additives, beverages, beverage additives, candies, suckers, pastilles, food supplements, sprays, injectables, and suppositories.
  • the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be provided as a salt, such as one or more salts of alkali metals, alkaline earth metals, transition metals, amino acids, or metabolites of amino acids.
  • Examples include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, zinc salts, iron salts (as iron II and/or iron III), chromium salts, manganese salts, cobalt salts, copper salts, molybdenum salts, selenium salts, arginine salts, lysine salts, leucine salts, isoleucine salts, histidine salts, ornithine salts, citrulline salts, glutamine salts, and creatine salts.
  • the non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate can be provided as one or more esters, such as mono-, di-, tri-, oligo-, and polyesters.
  • esters such as mono-, di-, tri-, oligo-, and polyesters.
  • Examples include mono-ester of ethanol, mono-ester of 1 -propanol, mono-ester of 1,2- propanediol, di-ester of 1,2-propanediol, mono-ester of 1,3-propanediol, di-ester of 1,3- propanediol, mono-ester of S-, R-, or S-R-l,3-butanediol, di-ester of S-, R-, or S-R-1,3- butanediol, mono-ester of glycerin, (3S)-hydroxybutyl (3S)-hydroxybutyrate mono-ester, (3R
  • the non-racemic mixture can include one or more salt forms of R-beta- hydroxybutyrate and S-beta-hydroxybutyrate in combination with a relatively minor amount of the acid form(s) of R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate.
  • the ratio of salt to acid forms of R-beta-hydroxybutyrate is not necessarily the same as the ratio of salt to acid forms of S-beta-hydroxybutyrate. This allows for more flexibility and a broader range of advantages in controlling the pharmacokinetics and electrolyte balance of the composition.
  • the non-racemic mixture contains less than 100% of one or more beta-hydroxybutyrate salts and greater than 0% free beta-hydroxybutyric acid, such as 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%, by molar equivalents of one or more R-beta-hydroxybutyrate and/or S-beta-hydroxybutyrate salts, 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%,
  • the non-racemic mixture contains a high amount of the R- enantiomer relative to the S-enantiomer
  • the non-racemic mixture can include one or more ester forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with a relatively minor amount of the acid form(s) of R-beta-hydroxybutyrate and/or S-beta- hydroxybutyrate.
  • the non-racemic mixture can include both salt and ester forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with a relatively minor amount of the acid form(s) of R-beta- hydroxybutyrate and/or S-beta-hydroxybutyrate.
  • the composition may include at least one medium chain fatty acid, or a mono-, di- or triglyceride of the 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 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.
  • the composition may include at least one long chain fatty acid having more than 12 carbons, or a mono-, di- or triglyceride of the 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 the medium chain fatty acid, or an ester thereof such as a medium chain triglyceride include coconut oil, coconut milk powder, fractionated coconut oil, palm oil, palm kernel oil, caprylic acid, capric acid, isolated medium chain fatty acids, such as isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid, medium chain triglycerides either purified or in natural form such as coconut oil, and ester derivatives of the medium chain fatty acids ethoxylated triglyceride, enone triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives, and triglyceride derivatives, and salts of the medium chain triglycerides.
  • Ester derivatives optionally include alkyl ester derivatives, such as methyl, ethyl, propyl, butyl, hexyl, etc.
  • a subject that has been administered an appropriate amount of a non-racemic mixture of R- beta-hydroxybutyrate and S-beta-hydroxybutyrate will be able to eat an occasional carbohydrate or sugar-based food without jeopardizing the ketogenic state and shifting back into a glucose-based metabolic state. Further, such administration facilitates easier transitioning into a ketogenic state while reducing or eliminating the detrimental effects typically associated with entering ketosis.
  • a ketogenic composition additionally includes a therapeutically effective amount of vitamin D3.
  • Vitamin D3 is believed to work in conjunction with magnesium and calcium to promote good bone health and to prevent undesirable calcification of soft tissues.
  • vitamin D3 is included in an amount such that an average daily dose of the ketogenic composition includes about 200 IU (“International Units”) to about 8000 IU, or about 400 IU to about 4000 IU, or about 600 IU to about 3000 IU of vitamin D3.
  • vitamin D3 is included in an amount such that an average daily dose of the ketogenic composition includes about 5 pg to about 200 pg, or about 10 pg to about 100 pg, or about 15 pg to about 75 pg of vitamin D3.
  • Some embodiments also include one or more additional ketone precursors or supplements.
  • additional ketone precursors or supplements might include acetoacetate, ketone esters, and/or other compounds that cause a rise in blood ketone levels without adding more electrolytes to the bloodstream.
  • Other additives include metabolites that enhance the effect or transport of ketone bodies into mitochondria, caffeine, theobromine, and nootropics, such as L-alpha glycerylphosphorylcholine (“alpha GPC”).
  • the composition may include flavoring agents that help mask the otherwise poor taste of beta-hydroxybutyrate compounds.
  • flavoring agents that help mask the otherwise poor taste of beta-hydroxybutyrate compounds.
  • These include essential oils, such as peppermint, natural and artificial sweeteners, and other flavorants known in the art.
  • ketogenic compositions may further include one or more additional components configured to lower the hygroscopicity of the composition.
  • additional components may include one or more of an aluminosilicate, ferrocyanide, carbonate or bicarbonate salt, silicate (e.g., sodium or calcium silicate), silica, phosphate salt (e.g., di- or tricalcium phosphate), talc, powdered cellulose, calcium carbonate, and the like.
  • compositions disclosed herein can be used in a method for increasing ketone body level, including promoting and/or sustaining 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.
  • beneficial effects of increasing ketone body level, including promoting and/or sustaining ketosis, in a subject include one or more of appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental alertness, increased physical energy, improved cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes, improvement of neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, antiglycation, reduction in epileptic seizer, improved mood, increased strength, increased muscle mass, or improved body composition.
  • Administering the non-racemic mixture of R-beta-hydroxybutyrate and S-beta- hydroxybutyrate in the enantiomeric ratios or percentages disclosed herein provides one or more of increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of the S-beta-hydroxybutyrate into one or both of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of the S-beta- hydroxybutyrate into fatty acids and sterols; prolonged ketosis; metabolism of the S- beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate; increased fetal development; increased growth years; reduced endogenous production of acetone during ketosis; signaling by the S-beta-hydroxybutyrate that modulates metabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-CoA.
  • Ketogenic compositions described herein may be administered to a subject in therapeutically effective dosages and/or in frequencies to induce or sustain ketosis.
  • a single dose will include an amount of non-racemic mixture of R- beta-hydroxy butyrate and S-beta-hydroxybutyrate ranging from about 0.5 gram to about 25 grams, or about 0.75 gram to about 20 grams, or about 1 gram to about 15 grams, or about 1.5 grams to about 12 grams.
  • the ketogenic compositions can include or be administered together with other supplements, such as vitamin D3, vitamins, minerals, nootropics, and others known in the art.
  • vitamins, minerals and herbal supplements that can be added to the ketogenic compositions include one or more of vitamin A, vitamin C, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese, chromium, caffeine, theobromine, theacrine, methylliberine, huperzine A, epicatechins, and enzymes.
  • compositions may further include one or more short chain fatty acids, medium chain fatty acids, long chain fatty acids, fatty acid esters, or mono-, di- or triglycerides of short, medium, or long chain fatty acids in order to provide an additional source of ketone bodies, as discussed herein, for sustaining ketosis for a longer period of time compared to the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate by itself.
  • the composition is preferably administered such that the ratio of the non-racemic mixture of R-beta- hydroxybutyrate and S-beta-hydroxybutyrate to short, medium, or long chain fatty acid (or ester thereof) ranges 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.
  • the subject preferably follows a ketogenic diet that restricts intake of carbohydrates and protein during the period of administration of the composition.
  • the subject may restrict the dietary intake to a ratio of about 65% fat, about 25% protein, and about 10% carbohydrates.
  • the resulting therapeutic ketosis provides a rapid and sustained keto-adaptation as a metabolic therapy for a wide range of metabolic disorders, and provides nutritional support for therapeutic fasting, weight loss, and performance enhancement.
  • the composition is typically administered once per day, twice per day, or three times per day to a subject desiring to promote and/or sustain a state of ketosis.
  • ketogenic compositions can be administered via oral administration in solid and/or powdered form, such as in a powdered mixture (e.g., powder filled gelatin capsules), hard-pressed tablets, or other oral administration route known to those skilled in the art.
  • a powdered mixture e.g., powder filled gelatin capsules
  • hard-pressed tablets e.g., hard-pressed tablets
  • 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 timing of treatment from previous treatments, objectives of the treatment, and the like.
  • the duration of administration of the composition e.g., the period of time over which the agent is administered, can vary depending on any of a variety of factors, including subject response, desired effect of treatment, etc.
  • the amount of the composition to be administered can vary according to factors such as the degree of susceptibility of the individual, the age, sex, and weight of the individual, idiosyncratic responses of the individual, and the like.
  • The“therapeutically effective amount” is that amount necessary to promote a therapeutically effective result in vivo (i.e., therapeutic ketosis).
  • a suitable single dose size is a dose that is capable of preventing or alleviating (reducing or eliminating) a symptom in a patient when administered one or more times over a suitable time period.
  • compositions administered will depend on potency, absorption, distribution, metabolism, and excretion rates of unused ketone bodies, electrolytes, the method of administration, and the particular disorder being treated, as well as other factors known to those of skill in the art.
  • the dose should be sufficient to affect a desirable response, such as a therapeutic or prophylactic response against 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 divided and administered over intervals of time. It is to be understood that administration may be adjusted according to individual need and professional judgment of a person administrating or supervising the administration of the compositions.
  • the compositions can be a blend of beta-hydroxybutyrate salts, blend of beta-hydroxybutyrate esters, blend of beta-hydroxybutyrate salts and esters, blend of beta-hydroxybutyrate salts and free beta-hydroxybutyric acid(s), blend of beta- hydroxybutyrate esters and free beta-hydroxybutyric acid(s), or blend of beta- hydroxybutyrate salts, beta-hydroxybutyrate esters, and free beta-hydroxybutyric acid(s), to provide a desired electrolyte balance, taste and/or pharmacokinetic response.
  • the compositions can also be combined with short, medium, or long chain fatty acids, esters, glycerides, and other supplements as disclosed herein to provide a desired level of elevated ketone bodies and other effects.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 49% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein.
  • the non-racemic mixture is readily administered as a ketogenic composition, such as 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.
  • a ketogenic composition such as 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.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 48% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 47% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 45% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 43% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixture of Examples 1-4.
  • including the S- beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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 equivalents of the R-beta-hydroxybutyrate enantiomer and 41% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-5.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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 equivalents of the R-beta-hydroxybutyrate enantiomer and 35% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-6.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 30% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-7.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 25% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-8.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 20% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-9.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 15% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-10.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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 equivalents of the R-beta-hydroxybutyrate enantiomer and 11% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
  • the non- racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-11.
  • including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein, as compared to a composition containing 90-100% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
  • 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 from 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 99.5% by enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer, with the proviso that the non-racemic mixture does not contain more than 88%, or 87%, or 86%, or 85% by enantiomeric equivalents of (3R)-hydroxybutyl (3R)- hydroxybutyrate
  • the non-racemic mixture includes more of the R-beta- hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture or the non-racemic mixtures of Examples 1-12.
  • any of the foregoing examples is modified by combining the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with a dietetically or pharmaceutically acceptable carrier.
  • any of the foregoing examples is modified by combining the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more medium chain triglycerides and/or one or more medium chain fatty acids and/or one or more mono- or diglycerides of medium chain fatty acids.
  • any of the foregoing examples is modified by combining the 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.
  • any of the foregoing examples is modified by combining the 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.
  • any of the foregoing examples is modified by combining the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more supplements, such as vitamin D 3 , vitamins, minerals, and others known in the art.
  • one or more supplements such as vitamin D 3 , vitamins, minerals, and others known in the art.
  • any of the foregoing examples is modified by including one or more salts of R- beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta- hydroxybutyric acid or S-beta-hydroxybutyric acid to provide a mixture of R- and S- beta-hydroxybutyrate salts and free R- and/or S-beta-hydroxybutyric acid(s), where the mixture contains less than 100% of the one or more beta-hydroxy butyrate salts and greater than 0% of the free beta-hydroxybutyric acid(s), 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 equivalents of one or more R-beta-hydroxybutyrate and at
  • Example 20 [0097] Any of the foregoing examples is modified by including 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 to provide a mixture of R- and S- beta-hydroxybutyrate ester forms and free R- and/or S-beta-hydroxybutyric acid(s), where the non-racemic mixture contains less than 100% of the one or more beta- hydroxybutyrate esters and greater than 0% free beta-hydroxybutyric acid.

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Abstract

Les compositions cétogènes comprennent un mélange non racémique de sels de bêta-hydroxybutyrate et d'un ou de plusieurs acides enrichis avec l'énantiomère R. Les compositions sont enrichies avec l'énantiomère R pour élever le taux de corps cétoniques et augmenter la vitesse à laquelle la cétose est atteinte, tout en contenant néanmoins une quantité de l'énantiomère S pour fournir d'autres avantages. L'acide bêta-hydroxybutyrique est plus rapidement absorbé et utilisé par le corps que les sels ou les esters, améliore le goût et réduit le besoin d'inclure de l'acide citrique ou d'autres acides comestibles. Les sels de bêta-hydroxybutyrate sont plus lentement absorbés et utilisés par le corps et peuvent fournir un ou plusieurs électrolytes. Les compositions pour l'augmentation du taux de corps cétoniques chez un sujet peuvent contenir un support diététiquement ou pharmaceutiquement acceptable et un mélange non racémique de R-bêta-hydroxybutyrate et de S-bêta-hydroxybutyrate, le mélange non racémique de R-bêta-hydroxybutyrate et de S-bêta-hydroxybutyrate contenant de 50,5% à 99,5% environ d'équivalents énantiomériques de R-bêta-hydroxybutyrate et de 49,5% à 0,5% environ d'équivalents énantiomériques de S-bêta-hydroxybutyrate.
PCT/US2020/017555 2019-02-11 2020-02-10 Composés bêta-hydroxybutyrate non racémiques et compositions enrichies avec l'énantiomère r, et leurs méthodes d'utilisation WO2020167692A1 (fr)

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CN202080013807.2A CN114025752A (zh) 2019-02-11 2020-02-10 富含R-对映体的非外消旋β-羟基丁酸根化合物和组合物以及使用方法
AU2020222897A AU2020222897A1 (en) 2019-02-11 2020-02-10 Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
EP20755289.4A EP3923924A4 (fr) 2019-02-11 2020-02-10 Composés bêta-hydroxybutyrate non racémiques et compositions enrichies avec l'énantiomère r, et leurs méthodes d'utilisation
JP2021546765A JP2022520203A (ja) 2019-02-11 2020-02-10 非ラセミ体のベータ－ヒドロキシブチレート化合物およびｒ－エナンチオマー富化組成物ならびに使用方法
CA3129587A CA3129587A1 (fr) 2019-02-11 2020-02-10 Composes beta-hydroxybutyrate non racemiques et compositions enrichies avec l'enantiomere r, et leurs methodes d'utilisation
JP2023171560A JP2023166026A (ja) 2019-02-11 2023-10-02 非ラセミ体のベータ－ヒドロキシブチレート化合物およびｒ－エナンチオマー富化組成物およびキット

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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
US16/409,501 2019-05-10
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
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