EP3923925A1 - Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use - Google Patents
Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of useInfo
- Publication number
- EP3923925A1 EP3923925A1 EP20755994.9A EP20755994A EP3923925A1 EP 3923925 A1 EP3923925 A1 EP 3923925A1 EP 20755994 A EP20755994 A EP 20755994A EP 3923925 A1 EP3923925 A1 EP 3923925A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- beta
- hydroxybutyrate
- racemic
- acid
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
-
- 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
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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
- 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
- administering the S-beta-hydroxybutyrate mixed salt-acid components along with the R-beta-hydroxybutyrate mixed salt-acid components in enantiomerically equivalent ratios 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 components into one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of the S-beta-hydroxybutyrate components into fatty acids and sterols; (4) prolonged ketosis; (5) metabolism of the S-beta- hydroxybutyrate components 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 components that modulates metabolism of
- Exogenous delivery of a racemic R, S-beta-hydroxybutyrate mixed salt-acid composition can beneficially provide a relatively rapid boost to blood ketone body levels, primarily by way of the R-beta-hydroxybutyrate mixed salt-acid components, particularly R-beta hydroxybutyric acid, in addition to a relatively more sustained addition to blood ketone body level primarily by way of the S-beta-hydroxybutyrate mixed salt-acid components.
- racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions described herein may be combined with (e.g., directly admixed with or co administered with) one or more other dietetically and/or pharmaceutically acceptable supplements/drugs to form a combination supplement.
- the unique properties of a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition may beneficially enhance the combination supplement as compared to an otherwise similar combination supplement using a beta-hydroxybutyrate composition consisting of or enriched with either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate.
- Embodiments include a “racemic stack” of at least four different beta- hydroxybutyrate compounds.
- R-beta-hydroxybutyrate and S-beta-hydroxybutyrate are provided as free acids (i.e., R-beta-hydroxybutyric acid and S-beta-hydroxybutyric acid), salts thereof (i.e., R-beta-hydroxybutyrate salt(s) and S -beta-hydroxy butyrate salt(s)), and optionally esters thereof (i.e., R-beta-hydroxybutyrate ester(s) and S-beta- hydroxybutyrate ester (s)).
- beta-hydroxybutyrate as a double racemic stack that combines at least four separate forms (or triple racemic stack that combines six separate forms) of beta-hydroxybutyrate may beneficially allow the use of higher amounts of beta-hydroxybutyrate for a given administered dose and/or allow for more doses per day.
- Each form of beta-hydroxybutyrate is typically associated with its own particular positive attributes and negative side effects. Stacking different forms of beta- hydroxybutyrate allows for delivery of more of the positive attributes compared to each being used alone. Similarly, stacking different forms of beta-hydroxybutyrate reduces or mitigates the negative side effects of each particular form of beta-hydroxybutyrate so that such negative effects can be “spread-out” and limited. In either case, stacking increases or maximizes the overall dose of beta-hydroxybutyrate that can be efficaciously delivered.
- Figure 1A illustrates higher levels of the amount of beta-hydroxybutyrate administered when using a“stacked” dose of at least two different forms of racemic R,S- beta-hydroxybutyrate as compared to single forms of racemic R,S-beta-hydroxybutyrate;
- Figure 2 compares expected release profiles of R,S-beta-hydroxybutyrate stack compositions to free acid, salt, and ester single forms and also an R-beta- hydroxybutyrate stack, illustrating that stacked R,S-compositions provide an overall release profile that is extended and has a larger area under the curve (AUC); and
- Figure 3 illustrates expected relative rates of lipolysis and/or fat oxidation resulting from treatment with a combination weight loss supplement including a beta- hydroxybutyrate component in combination with another weight loss supplement, and showing total amount of lipolysis and/or fat oxidation (area under the curve) is higher for a combination supplement using racemic R, S-beta-hydroxybutyrate components as compared to otherwise similar combination supplements/drugs using beta- hydroxybutyrate components enriched in R-beta-hydroxybutyrate or S-beta- hydroxybutyrate.
- beta-hydroxybutyrate also known as b-hydroxybutyrate, 3- hydroxybutyrate, bHB, or BHB
- beta-hydroxybutyric acid which is a hydroxycarboxybc acid having the general formula CH3CH2OHCH2COOH.
- the deprotonated form present at typical biological pH levels is CH3CH2OHCH2COO .
- the general chemical structure shown below represents beta-hydroxybutyrate compounds that may be utilized in the disclosed compositions:
- 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.
- racemic R,S-beta-hydroxybutyrate means there are enantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate in the composition.
- the terms “racemic R, S-beta-hydroxybutyrate salt” and “racemic R, S-beta- hydroxybutyrate salts” mean there are enantiomerically equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate salts in the composition.
- racemic R,S- beta-hydroxybutyric acid means there are enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyric acids in the composition.
- 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).
- beta-hydroxybutyric acid molecules can exchange protons and cations with dissolved beta-hydroxy butyrate salts.
- 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).
- 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.
- beta-hydroxybutyrate mixed salt- acid composition in a dry powdered state 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.
- 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.
- composition may optionally include 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate esters and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate esters.
- a racemic mixture of R,S-beta-hydroxybutyrate mixed salt-acid components can provide synergistic effects, such when used in combination with other components. In such case, the combined salt and acid forms of R, S-beta-hydroxybutyrate have acceptable pH and taste.
- R, S-beta-hydroxybutyrate mixed salt-acid compositions have substantial advantages over racemic R, S-beta- hydroxybutyrate salts and esters, including increased absorption rate, increased bioavailabibty, 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.
- the racemic R,S-beta-hydroxybutyrate mixed salt-acid composition contains less than 100% of racemic R,S-beta-hydroxybutyrate salts and greater than 0% of free racemic R,S-beta-hydroxybutyric acids.
- compositions are thus capable of effectively and relatively rapidly aiding a subject in inducing ketosis, while simultaneously providing for sustained and prolonged delivery of ketone bodies to the blood stream, wherein the R-beta-hydroxybutyrate and S-beta- hydroxy butyrate components together provide synergistic ketogenic benefits to a subject.
- the racemic R, S-beta-hydroxybutyrate mixed salt-acid composition contains an equivalent quantity of the S-beta-hydroxybutyrate enantiomer, which is not endogenously produced by a mammal, in order to produce one or more desired effects in the mammal.
- administering S-beta-hydroxybutyrate mixed salt-acid components along with R-beta-hydroxybutyrate mixed salt-acid components 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 components into one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of the S-beta-hydroxybutyrate components into fatty acids and sterols; (4) prolonged ketosis; (5) metabolism of the S-beta-hydroxybutyrate components 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
- Racemic R,S -beta-hydroxy butyrate mixed salt-acid compositions may optionally include racemic R,S-beta-hydroxybutyrate 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-l,3-butanediol, mono-ester of glycerin, (3S)-hydroxybutyl (3S)-hydroxybutyrate mono-ester, (3R)-hydroxy butyl (3S)-hydroxybutyrate, mono-ester, di-ester of glycerin, tri-ester of glycerin, ester of acetoacetate, dimers, trimers, oligomers, and polyesters containing repeating units of beta-hydroxybutyrate, and complex
- the composition may further include or be combined with 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.
- Example short chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid.
- An example short chain triglyceride is tributyrin. Such molecules can provide protection to the gut and improve microbiome health.
- the composition may include or be combined with at least one long chain fatty acid, or a mono-, di- or triglyceride of the at least one long chain fatty acid, having more than 12 carbons.
- 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.
- Raising the levels of ketone bodies in the blood through exogenous supplementation provides a subject with greater flexibility in diet options as compared to methods that aim to induce and sustain ketosis based on diet alone (e.g., based on fasting and/or limited carbohydrate intake).
- a subject that has been administered an appropriate amount of a racemic mixture of R-beta-hydroxybutyrate mixed salt-acid components and S-beta-hydroxybutyrate mixed salt-acid components 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.
- Acetoacetate can be provided in salt form, ester form, acid form, and combinations thereof.
- Other additives include metabolites that enhance the effect or transport of ketone bodies into mitochondria, caffeine, theobromine, and nootropics, such as L-alpha glycerylphosphorylchobne (“alpha GPC”).
- 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.
- ester forms of beta-hydroxybutyrate typically have poor organoleptic properties relative to the other forms of beta-hydroxybutyrate. That is, ester forms of beta-hydroxybutyrate are often described as having a pungent taste and/or smell.
- racemic R,S-beta-hydroxybutyrate i.e., racemic R,S-beta- hydroxybutyric acid
- racemic R,S-beta- hydroxybutyric acid is therefore utilized to form the mixed salt-acid compositions.
- beta-hydroxybutyric acid has a pKa of 4.70, it deprotonates and produces H + at physiological pH. The resulting excess acidity can cause undesirable side effects including causing or aggravating gastrointestinal issues such as ulcers or reflux.
- beta-hydroxybutyrate may be stacked in a single dose to allow for greater amounts of beta-hydroxybutyrate in the dose, and/or different forms of beta- hydroxybutyrate may be taken in different doses throughout the day to allow for greater dosing frequency and thus higher overall daily delivery of beta-hydroxybutyrate.
- a beta-hydroxybutyrate stack includes at least two of: (i) one or more R,S-beta-hydroxybutyrate salts; (ii) R,S-beta-hydroxybutyric acid; and (iii) one or more beta-hydroxybutyrate esters.
- a beta-hydroxybutyrate double stack may include at least two of components (i), (ii), and (iii) each provided at about 2% to about 98%, or about 5% to about 95%, or about, 10% to about 90%, or about 20% to about 80%, or about 30% to about 70%, or about 40% to about 60% on a molar basis of beta-hydroxybutyrate.
- a stacked beta-hydroxybutyrate composition may also provide a more beneficial digestive release profile.
- Each of the different forms of beta-hydroxybutyrate may interact somewhat differently upon ingestion.
- the free acid form may be readily delivered to the bloodstream as a usable ketone body
- beta-hydroxybutyrate from salt forms may in general take slightly longer to reach the bloodstream depending on the solubility characteristics of the particular salt or salt mixture utilized
- beta- hydroxybutyrate from ester forms may in general take the longest to reach the bloodstream depending on how rapidly the ester bond undergoes hydrolysis.
- keto stack compositions e.g., comprising the free acid and salt
- the keto stack compositions can provide more overall exogenous ketone bodies, and because they are provided in a plurality of different forms with different release characteristics, the overall release profile is extended and provides a larger AUC.
- Figure 2 also illustrates how a release profile may be adjusted by utilizing different relative amounts of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate.
- the beta-hydroxybutyrate in the “R Stack” is comprised of R-beta- hydroxybutyrate, while the “R/S Stack” contains a racemic mixture of R-beta- hydroxybutyrate and S-beta-hydroxybutyrate, which flattens and extends the release profile.
- a composition intended to increase lipolysis and/or fat oxidation may be combined with a racemic R,S- beta-hydroxybutyrate component to form a combination supplement with synergistic lipolysis and/or fat burning effects.
- a“fat burner” component a composition intended to increase lipolysis and/or fat oxidation
- a“fat burner” component may be combined with a racemic R,S- beta-hydroxybutyrate component to form a combination supplement with synergistic lipolysis and/or fat burning effects.
- the fat burner composition is more readily utilized when combined with a racemic R, S-beta-hydroxybutyrate component as compared to when utilized without a beta-hydroxybutyrate component. That is, the racemic R, S-beta-hydroxybutyrate component may function to effectively “prime” the subject for more metabolically efficient utilization of lipids as an energy source.
- the level of fat oxidation/lipolysis is more extended in duration than the enriched R-beta- hydroxybutyrate composition, but overall levels of fat oxidation/lipolysis remain relatively low throughout.
- the R- beta-hydroxybutyrate components and S-beta-hydroxybutyrate components function to provide a relatively high initial level of fat oxidation/lipolysis as well as a relatively extended duration of fat oxidation/lipolysis.
- acetylcholine modulators and/or adenosine receptor antagonists e.g., caffeine
- nicotine coca leaves
- coca leaves e.g., teas, extracts, isolates, salts, and free bases
- ursolic acid e.g., hordenine, atomoxetine
- 7- oxodehydroepiandrosterone i.e., 7-keto DHEA
- thyroid hormones e.g., triiodothyronine
- Exemplary compounds that may be included in the nootropic component include catecholamine precursors such as tyrosine, L-DOPA (i.e., L-3,4- dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP), racetams such as such as piracetam, oxiracetam, and aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors such as hordenine and atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvulus pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri, Epimedium herbs, Ashwagandha herbs, cyclic catecholamine precursor
- the ketogenic compositions can include or be administered together with other vitamin and/or mineral supplements, such as vitamin D3, and supplements for glucose control, such as berberine and other glucose lowering substances. It is postulated that a racemic mixture of R- and S-beta-hydroxybutyrate mixed salt-acid components can provide a longer lasting glucose lowering effect along with other substances.
- 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.
- 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 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.
- the ketogenic compositions can include or be administered together with other supplements, such as vitamin D 3 , 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.
- 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 in one or more unit doses per day 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
- an injectable may include one or more of mannitol, 1,3-butanediol, propylene glycol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid or Cremaphor.
- compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify, soften, and/or dissolve in the rectal cavity at body temperature to release the supplement.
- a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify, soften, and/or dissolve in the rectal cavity at body temperature to release the supplement.
- 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.
- a racemic R, S-beta-hydroxybutyrate mixed salt-acid composition is prepared by combining one or more R-beta-hydroxybutyrate salt compounds, one or more S-beta- hydroxybutyrate salt compounds, R-beta-hydroxybutyric acid, and S-beta- hydroxybutyric acid to provide 50% by enantiomeric equivalents of R-beta- hydroxybutyrate mixed salt-acid components and 50% by enantiomeric equivalents of S- beta-hydroxybutyrate mixed salt-acid components.
- the racemic mixture includes 50% by enantiomeric equivalents of R- beta-hydroxybutyrate mixed salt-acid compounds, the onset of ketosis is accelerated for a given dosage as compared to the same dosage enriched with S-beta-hydroxybutyrate compounds.
- the racemic mixture includes 50% by enantiomeric equivalents of S-beta-hydroxybutyrate mixed salt-acid compounds, the duration of sustained ketosis is increased for a given dosage as compared to the same dosage enriched with R-beta-hydroxybutyrate compounds.
- the racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of Example 1 is formulated to provide 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 racemic R,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%, 2.25%, 2.5%, 2.75%, or 3%, and less than 25%, 20%, 15%, 10%, 8%
- Example 1 or Example 2 is modified by combining the racemic R,S-beta- hydroxybutyrate mixed salt-acid composition with a dietetically (i.e., nutritionally) or pharmaceutically acceptable carrier.
- racemic R,S-beta- hydroxybutyrate mixed salt-acid composition with one or more short chain fatty acids, and/or one or more mono-, di- or triglycerides thereof, such as tributyrin.
- racemic R,S-beta- hydroxybutyrate mixed salt-acid composition with one or more long chain fatty acids, and/or one or more mono-, di- or triglycerides thereof.
- racemic R,S-beta- hydroxybutyrate mixed salt-acid composition with one or more supplements, such as vitamin D3, vitamins, minerals, and others known in the art.
- any of the foregoing examples is modified by combining the racemic R,S-beta- hydroxybutyrate mixed salt-acid composition with one or more fat burner supplements such as green tea, green tea extract (e.g., a composition including one or more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extract, conjugated linoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4-(4- hydroxyphenyl) butan-2-one, >-hydroxybenzyl acetone), ephedrine, synephrine (e.g., biter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulators and/or
- the resulting combined supplement is expected to provide greater lipolysis and/or fat oxidation effects than a similar dose utilizing a beta-hydroxybutyrate component enriched in R-beta-hydroxybutyrate or enriched in S-beta-hydroxybutyrate.
- the resulting combined supplement is expected to provide greater cognition, alertness, and/or mood effects than a similar dose utilizing a beta-hydroxybutyrate component enriched in R-beta-hydroxybutyrate or enriched in S-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.
Abstract
Description
Claims
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US16/720,211 US11020362B2 (en) | 2016-03-11 | 2019-12-19 | Beta-hydroxybutyrate mixed salt compositions and methods of use |
US16/783,956 US10973792B2 (en) | 2019-02-13 | 2020-02-06 | Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
PCT/US2020/017552 WO2020167690A1 (en) | 2019-02-11 | 2020-02-10 | Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
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US20220249497A1 (en) * | 2021-02-05 | 2022-08-11 | Health Via Modern Nutrition, Inc. | Compositions and methods for improving relaxation, sleep, cognition, and/or physical performance |
CN115251375A (en) * | 2022-07-11 | 2022-11-01 | 珠海麦得发生物科技股份有限公司 | (R) -3-hydroxybutyric acid ketonic product and preparation method thereof |
CN115153005A (en) * | 2022-07-27 | 2022-10-11 | 南京纽邦生物科技有限公司 | Beta-hydroxybutyric acid compositions |
WO2024067584A1 (en) * | 2022-09-27 | 2024-04-04 | 南京纽邦生物科技有限公司 | Complex of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate and preparation method therefor |
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JP2004035417A (en) | 2002-06-28 | 2004-02-05 | Kao Corp | Elevating drug for blood total ketone substance level |
EP2001293B9 (en) | 2006-04-03 | 2019-04-17 | Accera, Inc. | Use of ketogenic compounds for treatment of age-associated memory impairment |
CN105050594B (en) | 2013-03-19 | 2019-11-12 | 南佛罗里达大学 | For generating the composition and method that increase with lasting ketosis |
US10292952B2 (en) * | 2016-03-11 | 2019-05-21 | Axcess Global Sciences, Llc | Mixed salt compositions for maintaining or restoring electrolyte balance while producing elevated and sustained ketosis |
CA3021784A1 (en) * | 2016-04-19 | 2017-10-26 | Keto Patent Group, Inc. | Administration of butyrate, beta-hydroxybutyrate, and related compounds in humans |
WO2018017667A1 (en) | 2016-07-20 | 2018-01-25 | Sciadonics, Inc. | Lipid formulations containing bioactive fatty acids and other bioactive agents |
US10588877B2 (en) | 2016-07-21 | 2020-03-17 | Savind, Inc. | Compositions comprising β-hydroxybutyric acid and salt, and methods of using the same |
US20180057846A1 (en) * | 2016-08-30 | 2018-03-01 | KetoneAid Inc. | Partially buffered free acid and/or ketone blend for rapid onset ketosis and metabolic therapy |
WO2018114309A1 (en) | 2016-12-23 | 2018-06-28 | Katholieke Universiteit Leuven | 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment |
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