WO2020167571A1 - Beta-hydroxybutyrate mixed salt-acid compositions and methods of use - Google Patents
Beta-hydroxybutyrate mixed salt-acid compositions and methods of use Download PDFInfo
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- 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
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- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
Definitions
- Ketone bodies can be used by almost all cells of the body as a replacement fuel to satisfy the body's energy needs, including the needs of the brain and heart. During a prolonged fast, for example, blood ketone levels will increase to as high as 2 or 3 mmol/L or more.
- ketosis When blood ketones rise above 0.5 mmol/L, the heart, brain and peripheral tissues are using ketone bodies (beta-hydroxybutyrate and acetoacetate) as the primary fuel source. This condition is referred to as ketosis. At blood levels between 1.0 mmol/L and 3.0 mmol/L the condition is called“nutritional ketosis.”
- ketosis Upon transitioning into ketosis, during ketogenic metabolism in the liver, the body uses dietary and bodily fats as its primary energy source. During ketosis, one can lose body fat by controlling dietary fat intake and lowering carbohydrate intake to sustain ketosis. While in ketosis, the body is in ketogenisis and burning fat as primary fuel. The body cleaves fats into fatty acids and glycerol and transforms the fatty acids into acetyl-CoA molecules, which are then eventually transformed through ketogenisis into the water soluble ketone bodies beta-hydroxybutyrate, acetoacetate, and acetone in the liver. Beta-hydroxybutyrate and acetoacetate are 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 have beneficial impacts on physical, cognitive health, and psychological health, and a long-term impact on health with respect to common avoidable diseases such as obesity, cardiovascular disease, neurodegenerative diseases, diabetes, and cancer.
- ketogenic diet or lifestyle there remain significant barriers to pursuing and maintaining a ketogenic state.
- One of these is difficulty of transitioning into a ketogenic state.
- the fastest endogenous way to enter ketosis through depletion of glucose stores in the body is through fasting combined with exercise. This is physically and emotionally demanding and is extremely challenging even for the most motivated and disciplined.
- ketosis transition into ketosis is often accompanied by hypoglycemia, which can cause lethargy and light-headedness, resulting in an uncomfortable physiological and mental state commonly referred to as“low-carb flu.”
- hypoglycemia can cause lethargy and light-headedness, resulting in an uncomfortable physiological and mental state commonly referred to as“low-carb flu.”
- many people experience a down regulation in metabolism as the body goes into“energy-saving” mode. Some suggest these transitory symptoms may last as long as 2-3 weeks.
- any meal or snack consisting of carbohydrates over the restrictive amount is consumed, there is an immediate termination of ketogenisis and the body exits from a state of ketosis and shifts back to glucose utilization as its primary fuel. The transition into ketosis must then begin anew.
- ketosis If a subject is successful in establishing ketosis, sustaining ketosis is as or more difficult due to the need to maintain a rigid dietary ratio of carbohydrates and protein to fats. It is further complicated by disruption of normal electrolyte balance, which 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.
- Electrolyte imbalances can lead to fatigue, muscle cramping, headaches, dizziness, depression, constipation, skin problems, muscle weakness, and irritability, exacerbating other detrimental mental and physiological effects often associated with entering and maintaining a ketogenic state, thus further increasing the difficulty of promoting and/or sustaining ketosis.
- electrolyte imbalances can lead to serious health problems, such as heart palpitations, respiratory depression, involuntary muscle spasms, and cardiac arrhythmia.
- ketogenic compositions containing beta-hydroxybutyrate mixed salt-acid compositions formulated for inducing and/or sustaining ketosis in a subject while simultaneously promoting or maintaining a beneficial electrolytic balance.
- the ketogenic compositions may function to induce and/or sustain ketosis in a subject without delivering too much total electrolytes to the body, or too much of a particular electrolyte that may be unhealthy, such as excessive sodium, potassium, magnesium and/or calcium (/. e.. so as to not exceed the RDA for a particular electrolyte or only exceed it by a predetermined amount).
- beta-hydroxybutyrate mixed salt-acid compositions for promoting and/or sustaining ketosis in a subject include a beta-hydroxybutyrate mixed salt formed from a plurality of different cations and a quantity of free beta-hydroxybutyric acid.
- the cations can be selected from alkali metals, alkaline earth metals, transition metals, amines, and amino acids.
- Using a combination of cations and an amount of free beta- hydroxybutyric acid permits higher dosing of beta-hydroxybutyrate while maintaining or promoting electrolyte balance and/or without causing electrolyte imbalances or overload.
- a beta-hydroxybutyrate mixed salt-acid composition for promoting and/or sustaining ketosis in a subject includes a plurality of beta-hydroxybutyrate salts formulated from a plurality of cations.
- anions other than beta- hydroxybutyrate can be omitted from the mixed beta-hydroxybutyrate salt-acid compositions.
- the cations are formulated to provide a biologically balanced set of cationic electrolytes upon administration to the subject.
- the mixed salt-acid composition can include at least two of lithium beta-hydroxybutyrate salt, potassium beta-hydroxybutyrate salt, sodium beta-hydroxybutyrate salt (e.g., in an amount, by weight, that is no greater than an amount, by weight, of potassium beta-hydroxybutyrate salt), magnesium beta- hydroxybutyrate salt, and calcium beta-hydroxybutyrate salt (e.g., in an amount, by weight, that is no greater than an amount, by weight, of magnesium beta-hydroxybutyrate salt).
- Some embodiments include one or more transition metal salts, including but limited to beta-hydroxybutyrate salts, such as zinc salts, iron salts, copper salts, manganese salts, and chromium salts.
- beta-hydroxybutyrate salts such as zinc salts, iron salts, copper salts, manganese salts, and chromium salts.
- Other beta-hydroxybutyrate and non-beta-hydroxybutyrate salts include selenium salts and amino acid salts.
- a ketogenic composition is useful as a weight loss supplement, as a treatment for high blood glucose or type II diabetes, as a brain tonic, athletic performance enhancer, as a preventative against metabolic dysfunction, mitochondrial defect, insulin resistance, as an adjunct to a ketogenic diet, as an anti-aging supplement, and for other uses associated with improved metabolic health.
- the ketogenic composition is provided as a solid or powder form as opposed to a liquid or gel.
- Such solid-form ketogenic compositions in addition to providing the beneficial ketogenic and electrolyte balancing effects described herein, are preferably formulated to provide for ease of handling and manufacturability.
- the composition may be in the form of a liquid mouth spray for fast delivery and uptake.
- the beneficial ketogenic and electrolytic effects are realized without hampering or overly impacting the manufacturability or ease of handling of the composition.
- beta-hydroxybutyrate also known as b-hydroxybutyrate, 3- hydroxybutyrate, bHB, BHB, or beta-hydroxybutyrate
- beta-hydroxybutyric acid which is a hydroxycarboxylic 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 COOT
- 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 beta-hydroxybutyrate mixed salt-acid composition can include a mixture of beta-hydroxybutyrate salts and beta-hydroxybutyric acid.
- Providing beta-hydroxybutyrate in its acid form can be beneficial because of its much quicker absorption response time compared to salt forms. Nonetheless, even though the acid form by itself is a liquid with extremely low pH and unpalatable taste, when made or combined with salt forms and where the amount of beta-hydroxybutyric acid is small relative to the salt forms, the composition can still form a solid, powder or other form typical of salt forms. In such case, the combined salt and acid form of beta-hydroxybutyrate 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 beta-hydroxybutyrate 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).
- beta-hydroxybutyric acid molecules When dissolved in water, a portion of the beta-hydroxybutyric acid will typically dissociate into beta-hydroxybutyrate anions and hydronium ions (H 3 O+). As a result, beta- hydroxybutyric acid molecules can exchange protons and cations with dissolved beta- hydroxybutyrate 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).
- 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 a dry powdered state contained 5% of free non-deprotonated beta-hydroxybutyric acid and 95% beta-hydroxybutyrate salt(s) on a molar basis, there will 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 all of the beta-hydroxybutyrate salt(s), and if a portion of the beta-hydroxybutyric acid molecules are deprotonated, the molar equivalents of non-deprotonated beta-hydroxybutyric acid will be less than 5% and the molar equivalents of beta-hydroxybutyrate anions will be greater than 95%.
- the extent of deprotonation of beta-hydroxybutyric acid in solution is related to solution pH.
- Beta-hydroxybutyrate 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”.
- ketogenic composition refers to a mixed beta-hydroxybutyrate salt-acid composition.
- the 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, while simultaneously promoting or maintaining electrolyte balance in the subject.
- the term“mixed salt” or“multi-salt” is used herein to describe the portion of a ketogenic composition comprising multiple beta-hydroxybutyrate salts.
- the mixed BHB salts include a plurality of cation forms (e.g., two, three, four or more) of BHB salt, and the salts are relatively proportioned to promote electrolytic benefits in the subject.
- “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 for use 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 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 per se.
- SCT short chain triglycerides
- exemplary short chain faty 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 medium chain faty 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.
- beta-hydroxybutyrate mixed salt-acid compositions results in elevated and sustained blood levels of ketone bodies, thereby exploiting the metabolic and physiological advantages of sustained ketosis. Raising the levels of ketone bodies in the blood provides a subject with greater flexibility in diet options as compared to a method that aims to induce and sustain ketosis based on diet alone (e.g., based on fasting and/or limited carbohydrate intake). For example, a subject that has been administered an appropriate amount of beta-hydroxybutyrate mixed salt-acid 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.
- ketogenic state will often be in a state of electrolyte imbalance due to the metabolic shifts involved with ketosis, including enhanced diuretic effects and changes in insulin profiles.
- beta-hydroxybutyrate mixed salt-acid in order to promote or sustain ketosis in a subject
- the resulting electrolyte imbalance, and its associated detrimental physiological effects can offset the benefits of ketosis and/or make it more difficult for a subject to maintain ketosis at the desired levels or for a desired length of time.
- beta-hydroxybutyrate can be administered in salt form, where one or more beta-hydroxybutyrate molecules are the anions to a selected cation
- the introduction of additional cation electrolytes can cause or exacerbate electrolyte imbalance in a subject.
- a formulation having an overly high level and/or an overly high proportion of a particular form of beta-hydroxybutyrate salt can cause further electrolyte imbalance and/or cause other detrimental health effects.
- a formulation having an overly high level and/or an overly high proportion of sodium beta-hydroxybutyrate will increase levels of sodium in the subject. While sodium is a necessary nutrient, having levels that are outside of optimal ranges can lead to detrimental effects. High levels of sodium are associated with hypertension and poor cardiovascular health. In particular, high levels of sodium relative to potassium will promote hypertension and raise the risk of cardiovascular disease.
- a formulation having an overly high level or an overly high proportion of calcium beta-hydroxybutyrate will increase calcium levels in the subject. While calcium is also a necessary nutrient, and is particularly important for good bone health, excessive calcium may not be fully absorbed into the bones but may instead build up in soft tissues, leading to detrimental calcification and hardening of the tissues and raising the risk of heart disease (e.g., associated with hardened arteries), kidney stones, arthritis, and other problematic conditions. In particular, unduly high levels of calcium relative to magnesium can aggravate these negative effects. Magnesium functions by stimulating the hormone calcitonin and functions to convert vitamin D to its active form so it can promote calcium absorption in the bones as opposed to calcium deposition in soft tissues.
- beta-hydroxybutyrate salts in inappropriate amounts and proportions can therefore cause or aggravate detrimental health effects. Further, accounting for imbalances through other dietary options is not always easy or even possible for a subject attempting to maintain a ketogenic state. For example, many of the foods known to have high levels of potassium and/or magnesium, such as whole grains, bananas, avocados, milk, yogurt, oatmeal, com, peas, potatoes, and squash, contain high levels of carbohydrates and are not compatible with a strict ketogenic diet when consumed in any substantial amount.
- Embodiments disclosed herein provide a therapeutically effective amount of beta- hydroxybutyrate in the form of a beta-hydroxybutyrate mixed salt-acid.
- the beta-hydroxybutyrate mixed salt-acid is formulated to provide a biologically balanced set of cation electrolytes.
- One or more embodiments therefore provide the advantages of initiating and/or sustaining ketosis while simultaneously promoting positive electrolytic effects.
- the beta-hydroxybutyrate mixed salt-acid can include 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 beta-hydroxybutyrate mixed salt-acid includes a plurality of (e.g., at least two, three or four) different cations and is proportioned such that it comprises acceptable quantities and proportions of at least two of lithium beta- hydroxybutyrate, sodium beta-hydroxybutyrate, potassium beta-hydroxybutyrate, calcium beta-hydroxybutyrate, or magnesium beta-hydroxybutyrate.
- sodium beta-hydroxybutyrate is included in a range of about 5-70%, or about 6-50%, or about 8-40%, or about 10-30%, or about 12-25%, or about 14- 22%, or about 16-20%, or about 18%, by weight of the BHB mixed salt-acid.
- potassium beta-hydroxybutyrate is included in a range of about 5-70%, or about 6-50%, or about 8-40%, or about 10-30%, or about 12-25%, or about 14-22%, or about 16-20%, or about 18%, by weight of the BHB mixed salt-acid.
- calcium beta-hydroxybutyrate is included in a range of about 5-70%, or about 6-60%, or about 8-50%, or about 10-40%, or about 12-35%, or about 15- 30%, or about 18-25%, or about 20-23%, by weight of the BHB mixed salt-acid.
- magnesium beta-hydroxybutyrate is included in a range of about 5-70%, or about 6-60%, or about 8-50%, or about 10-40%, or about 12-35%, or about 15-30%, or about 18-25%, or about 20-23%, by weight of the BHB mixed salt-acid.
- sodium beta-hydroxybutyrate is included in an amount, by weight, no greater than an amount of potassium beta-hydroxybutyrate in the composition. This enables administration of necessary sodium and potassium electrolytes, providing a beneficial electrolytic effect to the subject, without causing or aggravating unwanted health effects associated with high sodium to potassium ratios (e.g., hypertension, cardiovascular disease, and other unfavorable effects).
- calcium beta-hydroxybutyrate is included in an amount, by weight, no greater than an amount of magnesium beta-hydroxybutyrate. This enables administration of necessary calcium and magnesium electrolytes, providing a beneficial electrolytic effect to the subject, without causing or aggravating unwanted health effects associated with high calcium to magnesium ratios (e.g., tissue calcification, poor bone health, and other unfavorable effects).
- beta-hydroxybutyrate mixed salt-acid compositions can be formulated such that the molar ratio of sodium to potassium ions is no greater than 1, and/or such that the molar ratio of calcium to magnesium ions is no greater than 1.
- the beta-hydroxybutyrate mixed salt-acid compositions disclosed herein comprise a plurality of beta-hydroxybutyrate salts and beta-hydroxybutyric acid. More particularly, the beta-hydroxybutyrate mixed salt-acid composition contains less than 100% of combined beta-hydroxybutyrate salts and greater than 0% free beta-hydroxybutryic 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 combined beta- hydroxybutyrate salts and at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%
- a ketogenic composition additionally includes a therapeutically effective amount of vitamin D3.
- Vitamin D3 works 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.
- the ketogenic compositions can include or be administered together with other supplements, such as 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
- 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”).
- Some embodiments include additional beta-hydroxybutyrate salts as part of the mixed salt of the ketogenic composition.
- some embodiments include one or more transition metal beta-hydroxybutyrate salts.
- Transition metal cations suitable for use as BHB or other salts include lithium, chromium, manganese, cobalt, copper, zinc, iron, (e.g., as an iron II or iron III cation), molybdenum, and selenium.
- the ketogenic composition can be formulated so that an average daily dose of the composition provides an amount of at least one of the cations of the mixed salt that is within a range of about 0.25 to about 10 times the recommended dietary allowance (RDA) of the of the at least one cation, or about 0.5 to 5 times, or about 0.75 to 2 times the RDA of the at least one cation.
- RDA recommended dietary allowance
- the mixed salt-acid composition may be formulated so that when a subject takes a daily amount of the composition, the subject will have consumed amounts cation electrolytes within the foregoing ranges.
- the mixed salt-acid composition is formulated so that the at least one cation electrolyte falling within the foregoing ranges after a daily dose of the composition is potassium and/or magnesium.
- RDA levels may be exceeded without necessarily experiencing toxicity or negative health effects.
- beta-hydroxybutyrate mixed salt-acid compositions may include one or more beta-hydroxybutyrate salts in which at least some of the cations are provided by one or more amino acids or other organic compounds that have a net positive charge at the pH at which the beta-hydroxybutyrate salts are produced beta- hydroxybutyrate-amino acid salts can provide soluble forms of beta-hydroxybutyrate without providing electrolytes, such as sodium, potassium, calcium or magnesium. This permits the manufacture of beta-hydroxybutyrate salts with a reduced quantity of electrolytes and/or healthier amount and/or healthier balance of electrolytes, particularly where it is desired to delivered higher quantities of beta-hydroxybutyrate for therapeutic reasons without further increasing electrolyte load.
- Suitable amino acids for this purpose can include amino acids that contain more than one amine group capable of being protonated to form a compound having a net positive charge, which can provide the counter cation for the beta-hydroxybutyrate anion.
- Examples include arginine, lysine, leucine, iso-leucine, histidine, ornithine, citrulline, L-glutamine, or other suitable amino acids or metabolites of amino acids (e.g., creatine).
- Some amino acids also provide health benefits. For example, /- arginine can increase nitric oxide in the blood, which dilates blood vessels and improves blood circulation for persons with heart conditions (and may help men suffering from erectile dysfunction).
- the ketogenic 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, where the short chain fatty acid has less than 6 carbons.
- 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 long chain fatty acid, or a mono-, di- or triglyceride of the at least one long chain fatty acid, having more than 12 carbons.
- 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.
- the ketogenic composition may be provided as a solid or powder form as opposed to a liquid or gel form.
- Such solid-form ketogenic compositions in addition to promoting beneficial ketogenic effects and electrolytic effects described herein, are formulated so as to provide for sufficient ease of handling and manufacturability.
- certain salts will exhibit different material properties (e.g., hygroscopicity), and the relative amounts of the different salts in the mixed salt formulation may affect the overall properties of the composition.
- the ketogenic composition may be provided as a liquid, such as in the form of a shot or mouth spray for fast delivery and absorption.
- Liquid forms may include one or more liquid carriers, such as water, ethanol, glycerin, propylene glycol, 1, 3-propandiol, and the like, into which the BHB mixed salt-acid compositions are dissolved or dispersed.
- the composition may include flavoring agents that help mask the taste of beta-hydroxybutyrate compounds. These include essential oils, such as peppermint, natural and artificial sweeteners, and other flavorants known in the art.
- beta-hydroxybutyrate salts in particular potassium beta- hydroxybutyrate and magnesium beta-hydroxybutyrate, exhibit greater hygroscopicity than other beta-hydroxybutyrate salts.
- Improperly proportioning beta-hydroxybutyrate salts can create formulations that do not flow or handle well, increasing manufacturing costs and potentially decreasing the shelf-life, stability and efficacy of the ketogenic composition product.
- compositions described herein can be formulated and balanced so as to provide the ketogenic and electrolyte benefits and advantages described above, while not unduly or unacceptably disrupting manufacturability of the composition.
- At least some embodiments include different beta-hydroxybutyrate salts in proportions that provide sufficient calcium BHB and/or sodium BHB (which typically promote manufacturability and handling) without overly including these salts at overly high levels which promote harmful health effects.
- at least some embodiments include potassium BHB and/or magnesium BHB (which typically hampers manufacturability and handling) in amounts sufficient to balance the calcium and/or sodium BHB but not in excessive amounts.
- the beta-hydroxybutyrate mixed salt-acid composition includes a dietetically or pharmaceutically acceptable carrier.
- a dietetically or pharmaceutically acceptable carrier examples include powders, liquids, tablets, capsules, food products, food additives, beverages, vitamin fortified beverages, beverage additives, candies, suckers, pastilles, food supplements, sprays, injectables, and suppositories
- 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.
- 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 beta-hydroxybutyrate mixed salt-acid ranging from about 1 -50 grams, or about 2-40 grams, or about 5-30 grams, or about 10-20 grams.
- the ketogenic compositions can include or be administered together with supplements or other additives described herein.
- 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.
- a ketogenic composition is administered orally, as in solid and/or powdered form, such as in a powdered mixture (e.g., powder filled gelatin capsules), hard-pressed tablets, dissolved in water or juice, or other oral administration route known to those skilled in the art.
- multiple doses of the composition can be administered.
- 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 beta-hydroxybutyrate and/or corresponding 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 effect 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 composition may be administered once, or it 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 composition.
- beta-hydroxybutyrate mixed salt-acid compositions useful for inducing and/or sustaining a ketogenic state in a subject to which they are administered while simultaneously providing a balanced set of cationic electrolytes.
- a beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 23% by weight, potassium BHB at 23% by weight, calcium BHB at 27% by weight, and magnesium BHB at 27% by weight. At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta- hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 18% by weight, potassium BHB at 18% by weight, calcium BHB at 32% by weight, and magnesium BHB at 32% by weight. At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta- hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 15% by weight, potassium BHB at 20% by weight, calcium BHB at 30% by weight, and magnesium BHB at 35% by weight. Vitamin D3 is added in an amount of 800 IU for every 20 grams of the BHB mixed salt-acid (representing an average daily dose). At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta-hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 15% by weight, potassium BHB at 15% by weight, calcium BHB at 35% by weight, and magnesium BHB at 35% by weight. At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta- hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 30% by weight, potassium BHB at 30% by weight, calcium BHB at 20% by weight, and magnesium BHB at 20% by weight. Vitamin D 3 is added in an amount of 1200 IU for every 15 grams of the BHB mixed salt-acid (representing an average daily dose). At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta-hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 15% by weight, potassium BHB at 15% by weight, calcium BHB at 18% by weight, magnesium BHB at 18% by weight, zinc BHB at 17% by weight, and iron BHB at 17% by weight.
- At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta-hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 20% by weight, potassium BHB at 20% by weight, calcium BHB at 20% by weight, magnesium BHB at 20% by weight, and zinc BHB at 20% by weight. At least one of the beta- hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta-hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 15% by weight, potassium BHB at 25% by weight, calcium BHB at 20% by weight, magnesium BHB at 25% by weight, and iron BHB at 15% by weight. At least one of the beta- hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta-hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 15% by weight, potassium BHB at 15% by weight, calcium BHB at 20% by weight, magnesium BHB at 20% by weight, zinc BHB at 20% by weight, and iron BHB at 10% by weight.
- Vitamin D3 is added in an amount of 600 IU for every 10 grams of the BHB mixed salt (representing an average daily dose).
- At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta- hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 or shot.
- a beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 23% by weight, potassium BHB at 23% by weight, calcium BHB at 27% by weight, and magnesium BHB at 27% by weight. At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta- hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid 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 beta-hydroxybutyrate mixed salt-acid is prepared by mixing sodium BHB at 25% by weight, potassium BHB at 25% by weight, calcium BHB at 25% by weight, and magnesium BHB at 25% by weight. At least one of the beta-hydroxybutyrate salts includes an amount of free beta-hydroxybutyric acid and/or an additional amount of free beta- hydroxybutyric acid is added to the BHB mixed salts to provide about 1-3% by weigh of free beta-hydroxybutyric acid.
- the BHB mixed salt-acid is mixed with an anti-caking agent, which is safe for human consumption, at a ratio of 4 to 1 to form a ketogenic composition readily administered to a subject, such as in powder form as a dietary supplement mixed with food or drink, or in the form of one or more capsules or tablets.
- any of the foregoing beta-hydroxybutyrate mixed salt-acid compositions includes at least one medium chain fatty acid source selected from a medium chain fatty acid having 6 to 12 carbons, preferably 8 to 10 carbons, mono glyceride of the medium chain fatty acid, diglyceride of the medium chain fatty acid, or triglyceride of the medium chain fatty acid to provide a ketogenic composition that provides prolonged ketosis over a greater period of time than would be provided by a given dosage of BHB mixed salt-acid by itself.
- the ratio of medium chain fatty acid source to BHB mixed salt-acid composition is 4:1, 3:1, 2:1, 1 :1 or 1 :2.
- any of the foregoing beta-hydroxybutyrate mixed salt-acid compositions includes one or more BHB salts of a cationic amino acid selected from arginine, lysine, leucine, iso leucine, histidine, ornithine, citrulline, L-glutamine, or metabolite of an amino acid, such as creatine).
- the BHB-amino acid salt decreases the ratio of electrolytes to BHB anions in the composition.
- any of the foregoing beta-hydroxybutyrate mixed salt-acid compositions is combined with at least one short chain fatty acid source selected from a short chain fatty acid having less than 6 carbons, monoglyceride of the short chain fatty acid, diglyceride of the short chain fatty acid, or triglyceride of the short chain fatty acid.
- any of the foregoing beta-hydroxybutyrate mixed salt-acid compositions is combined with at least one long chain fatty acid source selected from a long chain fatty acid having more than 12 carbons, monoglyceride of the long chain fatty acid, diglyceride of the long chain fatty acid, or triglyceride of the long chain fatty acid.
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CA3129411A CA3129411A1 (en) | 2019-02-11 | 2020-02-06 | Beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
EP20755770.3A EP3923918A4 (en) | 2019-02-11 | 2020-02-06 | Beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
JP2021546766A JP2022520560A (en) | 2019-02-11 | 2020-02-06 | Beta-Hydroxybutyrate Mixed Salt-Acid Composition and Usage |
CN202080027567.1A CN113660930A (en) | 2019-02-11 | 2020-02-06 | Beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
AU2020221031A AU2020221031A1 (en) | 2019-02-11 | 2020-02-06 | Beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
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US16/272,145 US10736861B2 (en) | 2016-03-11 | 2019-02-11 | Mixed salt compositions for producing elevated and sustained ketosis |
US16/720,211 US11020362B2 (en) | 2016-03-11 | 2019-12-19 | Beta-hydroxybutyrate mixed salt compositions and methods of use |
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WO2024067626A1 (en) * | 2022-09-27 | 2024-04-04 | 南京纽邦生物科技有限公司 | Composite of acid and salt, and preparation method therefor |
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US8758740B2 (en) * | 2007-03-30 | 2014-06-24 | Earthus, Inc | Composition for promoting ketone body production |
BR112015024186B1 (en) * | 2013-03-19 | 2023-05-09 | University Of South Florida | COMPOSITIONS AND METHODS FOR PRODUCING LIFT AND MAINTENANCE 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 |
US11173138B2 (en) * | 2016-04-19 | 2021-11-16 | Keto Patent Group, Inc. | Administration of butyrate, beta-hydroxybutyrate, and related compounds in humans |
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 |
WO2018187852A1 (en) * | 2017-04-12 | 2018-10-18 | Cavaleri Franco | Butyrate and beta-hydroxybutyrate compositions and methods of use thereof |
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US20160193173A1 (en) * | 2008-01-04 | 2016-07-07 | Isis Innovation Ltd. | Ketone bodies and ketone body esters as blood lipid lowering agents |
US20180021274A1 (en) * | 2016-07-21 | 2018-01-25 | Savind, Inc. | Compositions comprising beta-hydroxybutyric acid and salt, and methods of using the same |
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