WO2023081409A1 - Administration de métabolites de berbérine - Google Patents

Administration de métabolites de berbérine Download PDF

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Publication number
WO2023081409A1
WO2023081409A1 PCT/US2022/049036 US2022049036W WO2023081409A1 WO 2023081409 A1 WO2023081409 A1 WO 2023081409A1 US 2022049036 W US2022049036 W US 2022049036W WO 2023081409 A1 WO2023081409 A1 WO 2023081409A1
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Prior art keywords
beta
hydroxybutyrate
composition
administration
approximately
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PCT/US2022/049036
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English (en)
Inventor
Ryan LOWERY
Jacob Wilson
Shawn Wells
Original Assignee
Keto Patent Group, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US17/519,127 external-priority patent/US20220202789A1/en
Application filed by Keto Patent Group, Inc. filed Critical Keto Patent Group, Inc.
Publication of WO2023081409A1 publication Critical patent/WO2023081409A1/fr

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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
    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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

Definitions

  • the present invention relates to managing metabolic and therapeutic functions by administering berberine metabolites.
  • Berberine is a naturally occurring substance commonly found in Goldenseal (Hydrastis canadensis), Oregon grape (Berberis aquifolium), Barberry (Berberis vulgaris), Chinese Goldthread (Coptis chinensis, Phellodendron chinense, and Phellodendron amurense. Berberine has been administered to humans and found to have an effect on inflammation and as well as having some antimicrobial properties. Berberine has also shown potential for lowering fasting blood glucose; however adverse gastrointestinal effects appeared to accompany the administration in amounts to effectively lower fasting blood glucose (Yin et al. “Efficacy of Berberine in Patients with Type 2 Diabetes,” Metabolism. 2008 May; 57(5): 712-717).
  • one or more berberine metabolites may be administered to manage glucose tolerance and/or increase ketones (e.g., blood concentration and/or urine concentration of ketones) in humans.
  • ketones e.g., blood concentration and/or urine concentration of ketones
  • a pharmaceutically effective amount of berberine metabolites e.g., dihydroberberine and/or tetrahydroberberine
  • a pharmaceutically effective amount of berberine metabolites may be administered to a human with diabetes or other metabolic disorder impacting glucose tolerance.
  • the berberine metabolites may regulate glucose and/or lipid metabolism.
  • administration of a pharmaceutically effective amount of berberine metabolites may be therapeutic to humans with diabetes, glucose intolerance, metabolic syndrome, dyslipidemia, and/or obesity/overweight.
  • administration of berberine metabolites may have ergogenic (e.g., performance enhancing) and/or body composition benefits for some individuals (e.g., generally healthy; athletic; etc.) via glucose disposal, insulin sensitivity and ketone sensitivity.
  • administration of berberine metabolite(s) may lower glycation (e.g., measured by HAlc levels) which may provide anti-aging properties.
  • the berberine metabolite composition administered to an individual may include dihydroberberine and/or tetrahydroberberine.
  • the composition may be orally administered in any appropriate delivery vehicle, such as via tablets, capsules, food products, and/or beverage products.
  • one or more berberine metabolites may be administered with one or more additional compounds.
  • the additional compounds such as ketone sensitizers, may be capable of independently inducing ketosis.
  • the additional compounds may be utilized to maintain and/or promote ketosis in humans.
  • the additional compounds may include one beta-hydroxybutyrate compound; butyrate; short chain, medium chain, and/or long chain fatty acids or esters thereof; and/or combinations there of which may be administered with a berberine metabolite, such as dihydroberberine.
  • a pharmaceutically effective amount of dihydroberberine may be administered to an individual to managing glucose tolerance (e.g., decrease and/or maintain blood glucose level, decrease and/or maintain fasting blood glucose, increase ability to process glucose, etc.).
  • the administration of dihydroberberine may reduce fasting glucose levels.
  • the dihydroberberine may be administered as a complexed composition.
  • the complexed composition may include phytosomes and/or liposomes.
  • the dihydroberberine may be a microemulsion including dihydroberberine.
  • the pharmaceutically effective amount of dihydroberberine may include approximately 25 mg to approximately 800 mg of dihydroberberine, in some implementations.
  • the dihydroberberine may be orally administered as a capsule, tablet, a food product, and/or beverage product.
  • the dihydroberberine may be administered at least once daily (e.g., for a period of time, when desired by the user, etc.).
  • a Cytochrome P450 inhibitor may be administered approximately concurrently. Administration of the Cyctochrome P450 inhibitor may allow decreasing of the amount of dihydroberberine administered to be sufficient to achieve the desired results (e.g., the same level of glucose management as a predetermined amount of dihydroberberine, a normal range of fasting glucose levels per health guidelines, normal level of blood glucose level per health guidelines, etc.).
  • administering, to an individual, a pharmaceutically effective amount of dihydroberberine may increase blood ketone levels.
  • Implementations may include one or more of the following features.
  • the dihydroberberine may be administered approximately concurrently with meals.
  • a pharmaceutically effective amount of an additional compound may be administered with the dihydroberberine, where the additional compound is capable of inducing ketosis independently (e.g., ketone sensitizer).
  • the dihydroberberine and additional compound may be administered approximately concurrently.
  • the dihydroberberine and additional compound may be administered at least one time daily (e.g., for a period of time, per user desire, per doctor recommendation, until glucose level and/or blood ketone level is within a predetermined range, etc.).
  • composition may be capable of maintaining ketosis in an individual (e.g., within a predetermined time period of administration to the individual).
  • the composition may include a pharmaceutically effective amount of dihydroberberine and an additional compound (e.g., a compound that can impact blood ketone levels independently, such as a ketone sensitizer).
  • the amount of dihydroberberine administered to be pharmaceutically effective may be less than the amount of dihydroberberine administered to be pharmaceutically effective when the dihydroberberine is administered without the additional compound(s) (e.g., to achieve a predetermined level of ketosis and/or a range of blood ketone levels).
  • the additional compound(s) may include beta-hydroxybutyrate (e.g., R-beta-hydroxybutyrate and/or D,L- beta-hydroxybutyrate), butyrate, fatty acid, and/or ester of fatty acid.
  • the additional compound may include R-beta-hydroxybutyrate (e.g., salt, polymer, and/or complexed with another compound such as an amino acid).
  • the additional compound may include a beta- hydroxybutyrate salt, beta-hydroxybutyrate polymer, beta-hydroxybutyrate amino acid (e.g., R-beta-hydroxybutyrate amino acid mixture and/or complex, such as R-beta- hydroxybutyrate and leucine), and/or beta-hydroxybutyrate free acid(s).
  • the dihydroberberine and additional compound may be administered approximately concurrently.
  • the dihydroberberine and additional compound may be a mixture and/or a complexed compound.
  • the additional compound may include a beta-hydroxybutyrate and at least one of a fatty acid or ester of a fatty acid, in some implementations.
  • managing glucose tolerance in an individual may include administering, to an individual a pharmaceutically effective amount of a composition.
  • the composition may include approximately 25 mg to approximately 800 mg of dihydroberberine; beta-hydroxybutyrate, and at least one of a fatty acid or ester of a fatty acid.
  • Implementations may include one or more of the following features. Administration of composition may at least one of reduces fasting glucose levels, promote ketosis, and/or maintains ketosis in the individual.
  • the dihydroberberine may be administered as a complexed composition, and the complexed composition may include complexed phytosomes and/or liposomes.
  • the dihydroberberine may include a microemulsion including dihydroberberine.
  • the composition may be administered at least once daily.
  • the compound may include a Cytochrome P450 inhibitor. Administration of the Cyctochrome P450 inhibitor may allows decreasing of the amount of the composition administered to be sufficient to achieve the desired results.
  • the beta-hydroxybutyrate may include R-beta- hydroxybutyrate and/or a mixture of R-beta-hydroxybutyrate and L-beta-hydroxybutyrate.
  • the beta-hydroxybutyrate may include a beta-hydroxybutyrate salt and/or beta- hydroxybutyrate polymer.
  • the fatty acid may include a medium chain fatty acid, a short chain fatty acid, and/or a long chain fatty acid.
  • the fatty acid may include a medium chain fatty acid, a short chain fatty acid, and/or a long chain fatty acid such that an ester of the fatty acid may include ester of a medium chain fatty acid, ester of a short chain fatty acid, and/or ester of a long chain fatty acid.
  • the at least one of a fatty acid or ester of a fatty acid comprises at least one of coconut oil, coconut butter, or coconut milk.
  • managing glucose tolerance in an individual may include administering, to an individual a pharmaceutically effective amount of a composition.
  • the composition may include approximately 25 mg to approximately 800 mg of dihydroberberine and less than approximately 10 g of R-beta-hydroxybutyrate.
  • Implementations may include one or more of the following features.
  • the administration of composition may promote and/or maintain ketosis in the individual.
  • the R-beta-hydroxybutyrate may include at least 90 percent R-beta-hydroxybutyrate and less than 10 percent L-beta-hydroxybutyrate.
  • the R-beta-hydroxybutyrate may include a beta- hydroxybutyrate salt and/or beta-hydroxybutyrate polymer.
  • the composition may include one or more of additional compounds, such as a beta-hydroxybutyrate, a fatty acid, and/or ester of fatty acid.
  • the additional compounds may include an additional beta- hydroxybutyrate salt and/or beta-hydroxybutyrate polymer.
  • managing glucose tolerance in an individual may include administering, to an individual a pharmaceutically effective amount of R-beta- hydroxybutyrate, wherein the pharmaceutically effective amount of R-beta-hydroxybutyrate includes less than approximately 2g of R-beta-hydroxybutyrate.
  • Implementations may include one or more of the following features.
  • the R-beta- hydroxybutyrate may include at least 90 percent R-beta-hydroxybutyrate and less than 10 percent L-beta-hydroxybutyrate.
  • the R-beta-hydroxybutyrate may include a betahydroxybutyrate salt and/or beta-hydroxybutyrate polymer.
  • the administration of composition may promote and/or maintain ketosis in the individual.
  • a composition may be administered to managing glucose tolerance in an individual.
  • the composition may include approximately 5 g to approximately 15 g of beta-hydroxybutyrate, where the beta-hydroxybutyrate includes a R- beta-hydroxybutyrate salt.
  • Implementations may include one or more of the following features.
  • the administration of composition may induce or maintain ketosis in the individual.
  • the administration of composition may maintain or increase weight loss in the individual.
  • the composition may include at least one of leucine and at least one additional amino acid.
  • the composition may be administered via at a food or a beverage (e.g., the compound is included in the food or the beverage).
  • the composition may be powdered.
  • the powdered composition may dissolve in liquid for oral administration to the individual.
  • the composition may be orally administered via capsule and/or tablet (e.g., the composition may be disposed in the capsule and/or tablet).
  • a composition may be orally administered to maintain or increase weight loss in an individual.
  • the composition may include approximately 5 g to approximately 15 g of beta-hydroxybutyrate, where the beta-hydroxybutyrate includes one or more R-beta-hydroxybutyrate salts.
  • the composition may include one or more amino acids and/or one or more amino acid metabolites.
  • the composition may include leucine.
  • the composition may include approximately 0.5 to approximately 3 g leucine.
  • Administration of the composition may increase mental acuity in the individual.
  • Administration of the composition may increase metabolism, fat loss, fat oxidation, and/or muscle mass in the individual.
  • the composition may be administered up to 5 times daily.
  • the composition may include one or more of additional compounds (e.g., a fatty acid and/or ester of fatty acid).
  • the composition may include a vitamin, a mineral, an electrolyte, a flavoring, a binder, and/or a nutritional cofactor.
  • the composition may be administered via at a food or a beverage (e.g., the compound is included in the food or the beverage).
  • the composition may be powdered.
  • the powdered composition may dissolve in liquid for oral administration to the individual.
  • the composition may be orally administered via capsule and/or tablet (e.g., the composition may be disposed in the capsule and/or tablet).
  • orally administering a composition may induce or maintain ketosis in an individual.
  • the composition may include approximately 0.5 g to approximately 20 g of beta-hydroxybutyrate, where the beta-hydroxybutyrate includes one or more R-beta-hydroxybutyrate salts.
  • Implementations may include one or more of the following features.
  • the composition may include at least one amino acid.
  • the composition may include one or more of additional compounds capable of increasing or maintaining blood ketone levels.
  • the administration of the composition may increase mental acuity, motor function, and/or performance.
  • Figure 1 illustrates table with glucose levels for subjects after administration of an example administration protocol.
  • Figure 2 illustrates a table of subject responsiveness to an example administration protocol.
  • Figure 3 illustrates a table with blood ketone levels for subjects after administration of an example administration protocol.
  • Figure 4 a table with blood ketone levels for subjects after administration of an example administration protocol.
  • Figure 5 illustrates a table of blood ketone levels over time for 4 subjects for an implementation of an example administration of D,L-beta-hydroxybutyrate and R/D-beta- hydroxybutyrate.
  • Figure 6 illustrates a table of blood ketone levels over time for an implementation of an example administration of the microencapsulated butyrate compared to traditional sodium butyrate.
  • Figure 7 illustrates a chart including lifespan of rats subject to an implementation of an administration of R-beta-hydroxybutyrate.
  • Figure 8 illustrates a chart illustrating the results of motor skill testing following an implementation of an example administration protocol.
  • Figure 9A illustrates a chart illustrating fat loss results following an implementation of an example administration protocol.
  • Figure 9B illustrates a chart illustrating fat mass and lean mass results following an implementation of an example administration protocol.
  • Figure 10 illustrates a chart illustrating LPL levels in rats following an implementation of an example administration protocol.
  • Figure 11 illustrates a chart illustrating blood ketone levels following an implementation of an example administration protocol.
  • Figure 12 illustrates a chart illustrating improvement over a placebo following an implementation of an example administration protocol.
  • Figure 13 illustrates a chart illustrating perceived exertion following an implementation of an example administration protocol.
  • Figure 14 illustrates a chart illustrating blood ketone levels following an implementation of an example administration protocol.
  • Figure 15 illustrates a chart illustrating blood ketone levels following an implementation of an example administration protocol.
  • Figure 16A illustrates a chart illustrating RER levels following an implementation of an example administration protocol.
  • Figure 16B illustrates a chart illustrating RER levels following an implementation of an example administration protocol.
  • Figure 17A illustrates a chart illustrating perceived hunger following an implementation of an example administration protocol.
  • Figure 17B illustrates a chart illustrating perceived satiety following an implementation of an example administration protocol.
  • Figure 17C illustrates a chart illustrating perceived energy following an implementation of an example administration protocol.
  • Figure 18A illustrates a chart illustrating strength test results following an implementation of an example administration protocol.
  • Figure 18B illustrates a chart illustrating strength test results following an implementation of an example administration protocol.
  • Figure 18C illustrates a chart illustrating power results following an implementation of an example administration protocol.
  • Figure 19 illustrates a chart illustrating blood ketone levels following an implementation of an example administration protocol.
  • Figure 20 illustrates a chart illustrating blood ketone levels following an implementation of an example administration protocol.
  • administration of a pharmaceutically effective amount of berberine metabolites may be administered to humans to manage blood glucose levels (e.g., reduce fasting blood glucose, improve glucose tolerance, etc.).
  • administration of pharmaceutically effective amount of berberine metabolite(s) may maintain and/or increase ketone levels (e.g., blood and/or urine ketone concentration).
  • administration of a pharmaceutically effective amount of berberine metabolite(s) may be therapeutic to humans with diabetes, glucose intolerance, metabolic syndrome, dyslipidemia, and/or obesity/overweight.
  • administration of berberine metabolites may have ergogenic (e.g., performance enhancing) and/or body composition benefits for some individuals (e.g., generally healthy; athletic; etc.) via glucose disposal, insulin sensitivity and ketone sensitivity.
  • administration of a pharmaceutically effective amount of berberine metabolite(s) may lower glycation (e.g., measured by HAlc levels) which may provide anti-aging properties.
  • the amount of berberine metabolite (e.g., dihydroberberine) administered to achieve a predetermined effect may be less than the amount of berberine that would be required to achieve the same predetermined effect.
  • one or more other compounds may be administered with the pharmaceutically effective amount of berberine metabolite, such as a ketone sensitizer (e.g., a compound that is capable of reducing and/or maintaining blood ketone levels independently, such as betahydroxybutyrate, short chain fatty acids, medium chain fatty acids, and/or long chain fatty acids).
  • a ketone sensitizer e.g., a compound that is capable of reducing and/or maintaining blood ketone levels independently, such as betahydroxybutyrate, short chain fatty acids, medium chain fatty acids, and/or long chain fatty acids.
  • a berberine metabolite composition may include dihydroberberine and/or tetrahydroberberine.
  • Dihydroberberine C20H19NO4
  • ketone levels e.g., blood ketone levels
  • Dihydroberberine is a compound that is commercially available from sources such as, AdooQ Bioscience (Irving, CA).
  • Dihydroberberine may be more biologically available to humans than berberine.
  • a first weight amount of dihydroberberine is capable of decreasing blood glucose levels greater than the same weight amount of berberine.
  • a first weight amount of dihydroberberine may increase blood ketone levels more than the same weight amount of berberine.
  • ketosis may improve metabolic disorders, improve health (e.g., strength, mental acuity, etc.), increase weight loss, and/or increase fat loss (e.g., as opposed to lean muscle mass loss).
  • Diabetes various types of cancer, Alzheimer’s, Parkinson’s, Traumatic Brain Injury (TBI) PCOS, Metabolic Syndrome/Syndrome X, Obesity, Dyslipidemia, Aging, other metabolic disorders and/or other ketosensitive diseases and/or disorders may thus be affected by administration of dihydroberberine or tetrahydroberberine (e.g., since ketosis may be more easily achieved by individuals in which dihydroberberine has been administered).
  • TBI Traumatic Brain Injury
  • the berberine metabolite may include tetrahydroberberine (C20H21O4N).
  • Tetrahydroberberine is a compound that although related to berberine has properties that make it especially suited for managing glucose and/or increasing ketone levels (e.g., blood ketone concentration).
  • dihydroberberine and/or tetrahydroberberine may be complexed with other compounds such as phytosomes and/or liposomes.
  • the berberine metabolite may be administered to a user via the complexed compound.
  • a pharmaceutically effective amount of berberine metabolite may be administered to humans to improve glucose tolerance.
  • an amount of approximately 25 mg to approximately 800 mg of dihydroberberine may be administered to a human.
  • an amount of approximately 250 mg to approximately 300 mg may be administered to a human.
  • the amount of dihydroberberine may be less than the amount of berberine required to achieve the same amount of glucose tolerance (e.g., a predetermined fasting glucose level, a predetermined range of blood glucose, a normal or other blood gluocose level as determined by health guidelines, a normal or other fasting blood gluose as determined by health guidelines, etc.).
  • an amount of dihydroberberine may provide the same level of glucose tolerance as at least double the same amount of berberine (e.g., the dihydroberberine may be at least twice as effective as berberine and thus half or less than half of a first amount of dihydroberberine would be required to achieve the same results as the first amount of berberine).
  • This result is unexpected since one would expect berberine and dihydroberberine to have similar properties. Even with the known increase bioavailability of dihydroberberine over berberine, the ability to administer as little as half as much dihydroberberine as berberine to achieve similar results in glucose tolerance is unexpected.
  • the ability to reduce the quantity of dihydroberberine administered to a human may reduce the side effects associated with administration, ease palatability (e.g., since taste may improve or be more easily masked with smaller dosages), ease administration (e.g., smaller dose size), reduce costs, etc.
  • ease palatability e.g., since taste may improve or be more easily masked with smaller dosages
  • ease administration e.g., smaller dose size
  • reduce costs etc.
  • the same amount (e.g., molecular amount) of the “berberine” group is in berberine and dihydroberberine
  • decreasing the amount administered would decrease side effects associated with administration of berberine and/or related complexes.
  • one or more additional compounds may be administered with the berberine metabolite.
  • the additional compounds may increase a benefit of the berberine metabolite (e.g., glucose management, decrease ketone levels, etc.) and/or provide additional benefits (e.g., increase mental acuity, increase fat loss, increase lean mass maintenance, increase strength, etc.)
  • additional compounds e.g., increase mental acuity, increase fat loss, increase lean mass maintenance, increase strength, etc.
  • an additional compound that is capable of impacting blood ketone levels e.g., increasing and/or maintaining blood ketone levels, inducing ketosis, etc.
  • a ketone sensitizer may be selected that increases ketosis (e.g., increase levels of ketones bodies in the blood).
  • the additional compounds may include a beta-hydroxybutyrate compound may be administered with the berberine metabolite (e.g., in a capsule such as a softgel; tablet; powdered supplement; ready-to-drink formulation; topical product; cosmeceutical product; foods such bars, cookies, gum, candy, functional foods; toothpaste, sublingual product; injection; intravenous fluids; beverages such as shots or energy shots; inhalers and/or other appropriate administration methods).
  • a beta-hydroxybutyrate compound may include beta-hydroxybutyrate salts, beta- hydroxybutyrate monomer, beta-hydroxybutyrate polymers, and/or combinations thereof.
  • beta-hydroxybutyrate salts may include sodium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate, calcium beta-hydroxybutyrate, lithium beta- hydroxybutyrate, potassium beta-hydroxybutyrate and/or combinations thereof.
  • beta-hydroxybutyrate polymers may be selected for administration with dihydroberberine to administer beta-hydroxybutyrate (e.g., since beta-hydroxybutyrate polymers are metabolized in the body to administer beta-hydroxybutyrate).
  • the beta-hydroxybutyrate administered may include organic salts, such as but not limited to, arginine beta-hydroxybutyrate, lysine beta-hydroxybutyrate, histidine beta-hydroxybutyrate, ornithine beta-hydroxybutyrate, creatine beta-hydroxybutyrate, agmatine beta-hydroxybutyrate, citrulline beta-hydroxybutyrate, and/or combinations thereof.
  • the beta-hydroxybutyrate included in the composition may include R-beta- hydroxybutyrate (e.g., salts, polymers, complexes, etc.).
  • the beta-hydroxybutyrate may include single isomer R-beta-hydroxybutyrate and/or polymer R-beta-hydroxybutyrate.
  • beta-hydroxybutyrate may be administered with 1,3 -butanediol, ethyl acetoacetate, ethyl beta-hydroxybutyrate.
  • the additional compound e.g., that is capable of increasing blood ketone levels independently
  • the additional compound may include a fatty acid and/or ester thereof.
  • the additional compound may include short chain, medium chain, and/or long chain fatty acids and/or esters thereof.
  • the fatty acid(s) and/or esters thereof may include natural and/or synthesized compounds.
  • the additional compound may include coconut oil, butter, coconut milk, etc.
  • the additional compound may be in any appropriate form (e.g., emulsion, liquid, powder, etc.).
  • the composition may include more than one additional compound that is capable of increasing blood ketone levels and/or inducing ketosis independently (e.g., without dihydroberberine).
  • a medium chain fatty acid may be administered with the berberine metabolite and/or beta-hydroxybutyrate compound.
  • an amino acid may be administered with dihydroberberine and R- beta-hydroxybutyrate (e.g., salt, polymer, and/or complex).
  • a composition may be administered as described that includes berberine metabolites (e.g,. Dihydroberberine, tetrahydroberberine, etc.) and/or an additional compound that increases ketone levels (e.g., blood and/or urine), such as a ketone sensitizer.
  • the additional compound(s) may include one or more beta-hydroxybutyrate compounds, short chain triglycerides, medium chain triglycerides, long chain triglycerides, combinations thereof and/or derivatives thereof.
  • one or more of the beta- hydroxybutyrate compounds and/or other ketone sensitizers may be utilized as a ketone sensitizer.
  • ketone sensitizers e.g., short chain triglycerides, medium chain triglycerides, long chain triglycerides
  • an amount of an additional compound e.g., capable of increasing ketone levels and/or inducing ketosis independently
  • berberine metabolite(s) e.g., Dihydroberberine, tetrahydroberberine, etc.
  • an additional compound e.g., capable of increasing ketone levels and/or inducing ketosis independently
  • berberine metabolite(s) e.g., Dihydroberberine, tetrahydroberberine, etc.
  • berberine metabolite(s) e.g., Dihydroberberine, tetrahydroberberine, etc.
  • blood ketone levels may rise.
  • less of the additional compound may be administered to achieve a predetermined blood ketone level (e.g., to maintain and/or promote a state of ketosis).
  • an additional compound such as 10 grams of sodium beta-hydroxybutyrate may be administered to a 200 pound human to achieve a first level of ketosis (e.g., blood ketone level of 0.5mM).
  • the amount of the additional compound may be decreased.
  • 3 milligrams of sodium beta-hydroxybutyrate may be administered to achieve the first level of ketosis rather than 10 grams of sodium beta-hydroxybutyrate.
  • Administration of the additional compound may cause increase user satisfaction (e.g., less side effects from increased amounts of the additional compound and/or cation when salts of the additional compounds are included) and/or decreases costs (e.g., since less of the additional compound may be utilized), and enhance endogenous production (e.g. since blood glucose is lower, endogenous ketones may be elevated alongside the exogenous ketones)
  • the berberine metabolite(s) e.g., dihydroberberine tetrahydroberberine, etc.
  • the additional compound e.g., capable of increasing ketone levels in the blood
  • the dihydroberberine and ketone sensitizer may be provided in a capsule, pill, granular form (e.g., packet of granules), powdered form, liquid, gel, sublingual, transdermal and/or any other appropriate administration form.
  • one or more additives may be included in the composition, such as flavorings (e.g., natural and/or artificial), vitamins, minerals, binders, and/or any other appropriate additive.
  • the additives may alter flavor, color, and/or texture.
  • the additives may increase palatability and/or facilitate inclusion in a delivery vehicle (e.g., tablet, food product, beverage product such as a drink mix, etc.).
  • a delivery vehicle e.g., tablet, food product, beverage product such as a drink mix, etc.
  • the berberine metabolite(s) may be processed to increase bioavailability, solubility, palatability, and/or combination with other compounds.
  • berberine metabolite(s) may be processed to form a microemulsion with other compounds (e.g., ketone sensitizer, liposome, phytosome, flavorings, etc.).
  • the berberine metabolite may be microencapsulated (e.g., with and/or without other compounds such as ketone sensitizer, liposome, phytosome).
  • Microemulsions may improve bioavailability and solubility as well as other agglomeration technologies.
  • the microencapsulated berberine metabolite(s) may be a free flowing granular powder; dispersible in water; stable in acidic water solution for 30 minutes; allow controlled release in stomach and/or small intestines; inhibit glucose response (e.g., to any added materials); and/or allow delivery of a high butyrate content (e.g., around 70%), in some implementations.
  • the berberine metabolite may be complexed with another compound (e.g., liposome, phytosome, and/or combinations thereof) and the berberine metabolite complex may be administered to the user to administer the berberine metabolite.
  • Bioavailability enhancement via the mechanism of action for Cytochrome P450 inhibitors like naringen, bergamotin, piperine and its metabolites, as well as other bioavailability enhancers may be co-administered to enhance efficacy at lower therapeutic doses. Lowering the therapeutic dosage may decrease side effects and/or costs.
  • the berberine metabolite(s) e.g,. Dihydroberberine, tetrahydroberberine, etc.
  • the berberine metabolite(s) and/or other compounds administered with the dihydroberberine may be administered on an appropriate administration schedule.
  • the Dihydroberberine/tetrahydroberberine and/or other compounds may be administered concurrently with meals, a predetermined amount of time before meals, a predetermined amount of time after meals, at regular or irregular time intervals, and/or according to other appropriate administration schedules.
  • the berberine metabolite composition e.g., including the berberine metabolite
  • the berberine metabolite composition may be administered to achieve a predetermined blood gluocose level and/or fasting level.
  • the administration of the composition (e.g., in the same and/or lower dosage) may be continued and/or discontinued once the predetermined level is achieved.
  • the berberine metabolite composition may be administered as desired by a user in some implementations (e.g., to facilite achieving user goals such as in strength training, for performance, for insurance testing, etc.).
  • the amount of Dihydroberberine/tetrahydroberberine and/or other compounds administered at each dose may be the same and/or different.
  • the composition administered to an individual may include approximately 5 mg to approximately 1 gram of dihydroberberine.
  • the composition may include one or more other compounds that may or may not be capable of increasing blood ketone levels independently, in some implementations.
  • the composition may be administered (e.g., orally) approximately 1 to approximately 3 times daily.
  • the composition may be provided in a delivery form such powder (e.g,. that capable consumed separately, mixed with drinks, and/or food) and/or tablet.
  • the administration of the composition may maintain ketosis levels for approximately 30 min to approximately 3 hours.
  • the administration of the composition may maintain ketosis for longer than 3 hours.
  • the administration of the composition may maintain blood glucose levels within a healthy range (e.g., as determined by a doctor, health guidelines, insurance guidelines, etc.).
  • the administration of the composition may decreases blood glucose levels during a glucose challenge testing by over 25%, in some implementations.
  • the administration of the composition may be capable of maintaining approximately 2 to approximately 3 times greater elevated ketones during carbohydrate intake (e.g., when compared with berberine and/or when compared with individuals not being administered dihydroberberine).
  • the administration of the composition may increased fat metabolism by 10% (e.g., when compared with the individuals capability without administration of dihydroberberine).
  • the compound may include dihydroberberine and a betahydroxybutyrate.
  • the composition may include one or more other compounds that may or may not be capable of increasing blood ketone levels independently, in some implementations.
  • the composition may include approximately 5 mg to approximately 1 g of dihydroberberine and approximately 2 g of beta-hydroxybutyrate to approximately 10 g of beta-hydroxybutyrate.
  • the composition may include approximately 400 mg to approximately 600 mg of dihydroberberine (e.g., approximately 500 mg) and approximately 4 to approximately 7 g of beta-hydroxybutyrate (e.g., 5 g of beta-hydroxybutyrate, such as R-beta-hydroxybutyrate).
  • the composition may be administered (e.g., orally) approximately 1 to approximately 3 times daily.
  • the composition may be provided in a delivery form such powder (e.g,. that capable consumed separately, mixed with drinks, and/or food) and/or tablet.
  • the combination of dihydroberberine and additional compounds that are capable of increasing ketones independently, such as beta-hydroxybutyrate, may increase ketones at a greater level than the expected additive amount.
  • a composition of 500 mg of dihydroberberine and 5 grams of beta-hydroxybutyrate and 5 grams of short chain triglyceride may increase ketones over 1 mM (e.g., while 5 grams of BHB alone elevate blood ketone levels to only 0.5mM)
  • the dihydroberberine may be complexed or otherwise coupled to one or more of the additional compounds in the composition.
  • the composition may include a dihydroberberine - beta-hydroxybutyrate complex and/or a dihydroberberine - amino acid complex.
  • administration of dihydroberberine may maintain and/or improve memory functions, cognitive functioning, brain health, telomere health, and/or combinations thereof.
  • Administration of dihydroberberine may improve and/or maintain mood and/or psycological health.
  • Administration of dihydroberberine may provide neuroprotection.
  • Administration of dihydroberberine may promote longevity. For example, administration of approximately 25 mg to approximately 800 mg of dihydroberberine may improve brain health (e.g., memory, cognitive function, general health, telomere health, etc.).
  • other additional compounds e.g., fatty acids, esters of fatty acids, beta-hydroxybutyrate, R-beta-hydroxybutyrate, as previously described, may be administered with the dihydroberberine.
  • dihydroberberine may be utilized independently and/or in conjunction with additional compounds to manage glucose tolerance, reducing fasting glucose levels; maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels); and/or promote and/or maintain weight loss.
  • dihydroberberine, beta-hydroxybutyrate, and at least one of a fatty acid or an ester of a fatty acid may be administered to manage glucose tolerance, reducing fasting glucose levels, and/or maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels).
  • the individual may be administered dihydroberberine, betahydroxybutyrate, and a triglyceride.
  • dihydroberberine and R- beta-hydroxybutyrate may be administered to manage glucose tolerance, reducing fasting glucose levels, and/or maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels).
  • R-beta-hydroxybutyrate may be administered to manage glucose tolerance, reducing fasting glucose levels, and/or maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels).
  • at least approximately 25 mg and less than approximately 800 mg of dihydroberberine may be administered.
  • the dihydroberberine may be any appropriate form of dihydroberberine.
  • beta-hydroxybutyrate may include racemic mixtures and/or individual isomers of betahydroxy -butyrate (e.g., approximately 100% R- beta-hydroxybutyrate; 90% R- beta-hydroxybutyrate and 10% L- beta-hydroxybutyrate; at least 90% R- beta-hydroxybutyrate and less than 10% L- beta-hydroxybutyrate).
  • salts, polymers, esters, complexes, or combinations thereof of beta- hydroxybutyrate may be administered.
  • At least 0.1 g and less than 50 g of fatty acid and/or ester of fatty acid may be administered.
  • the fatty acids and/or esters may include natural (e.g., cream, coconut oil, macadamia oil, etc.) and/or artificial fatty acids and/or esters of fatty acids.
  • the composition may include a short chain fatty acid, an ester of short chain fatty acid, a medium chain fatty acid, an ester of medium chain fatty acid, a long chain fatty acid, or an ester of long chain fatty acid.
  • dihydroberberine, beta-hydroxybutyrate, and at least one of a fatty acid or an ester of a fatty acid may be administered to manage glucose tolerance, reducing fasting glucose levels, and/or maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels).
  • the individual may be administered dihydroberberine, beta-hydroxybutyrate, and a triglyceride.
  • dihydroberberine and R-beta-hydroxybutyrate may be administered to manage glucose tolerance, reducing fasting glucose levels, and/or maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels).
  • R-beta-hydroxybutyrate may be administered to manage glucose tolerance, reducing fasting glucose levels, and/or maintain and/or promote ketosis (e.g., maintain and/or increase blood ketone levels).
  • ketosis e.g., maintain and/or increase blood ketone levels.
  • R- betahydroxybutyrate may be administered to increase and/or maintain glucose tolerance and/or ketosis (e.g., increase and/or maintain blood ketone levels).
  • administration of R- beta-hydroxybutyrate may promote and/or maintain weight loss.
  • the R-beta-hydroxybutyrate may include L-beta-hydroxybutyrate, in some implementations.
  • the composition administered may include at least approximately 90% R-beta- hydroxybutyrate and less than 10% approximately L-beta-hydroxybutyrate.
  • one or more additional compounds, as described herein and in U.S. Patent Application No. 15/491,924 may be administered with the R-beta-hydroxybutyrate to maintain glucose tolerance, decrease fasting glucose, promote ketosis, maintain ketosis, promote weight loss, and/or maintain weight loss.
  • compounds such as butyrate, beta-hydroxybutyrate and/or related compounds (e.g., derivatives, esters, polymers, etc.) can be administered alone or in combination with one or more other compounds. Administration of a pharmaceutically effective amount of these compound(s) may promote and/or maintain weight loss and/or ketosis. In some implementations, blood ketone levels and/or blood glucose levels may be reduced and/or maintained within a predetermined range when a pharmaceutically effective amount of one or more compounds are administered.
  • a health of an individual may be improved and/or maintained by administration of a compound that includes butyrate, beta-hydroxybutyrate and/or related compounds (e.g., derivatives, esters, polymers, etc.).
  • a compound that includes butyrate, beta-hydroxybutyrate and/or related compounds e.g., derivatives, esters, polymers, etc.
  • Beta-hydroxybutyrate e.g., R-beta- hydroxybutyrate, L-beta-hydroxybutyrate, and/or D, L-beta-hydroxybutyrate
  • Beta-hydroxybutyrate salts and/or beta-hydroxybutyrate esters may include beta-hydroxybutyrate salts and/or beta-hydroxybutyrate esters.
  • beta-hydroxybutyrate may include beta-hydroxybutyrate bound to another compound (e.g., amino acids) and/or polymers of beta-hydroxybutyrate.
  • beta-hydroxybutyrate may include beta-hydroxybutyrate salts, beta-hydroxybutyrate esters, beta-hydroxybutyrate sodium salt (e.g., sodium beta-hydroxybutyrate), beta-hydroxy butyrate potassium salt (e.g., potassium beta-hydroxybutyrate), beta-hydroxybutyrate calcium salt (e.g., calcium beta- hydroxybutyrate), beta-hydroxybutyrate magnesium salt (e.g., magnesium beta- hydroxybutyrate), beta-hydroxybutyrate lithium salt (e.g., lithium beta-hydroxybutyrate), sodium beta-hydroxybutyrate, arginine beta-hydroxybutyrate, lysine beta-hydroxybutyrate, histidine beta-hydroxybutyrate, ornithine beta-hydroxybutyrate, creatine beta- hydroxybutyrate, agmatine beta-hydroxybutyrate
  • the beta-hydroxybutyrate may include beta-hydroxybutyrate salts including (calcium, sodium, magnesium, potassium, zinc, selenium, chromium, other appropriate minerals, and/or combinations thereof.
  • the beta- hydroxybutyrate may be complexed and/or coupled to another compound (e.g., amino acid and/or berberine) and a beta-hydroxybutyrate salt may include a complex (e.g., chelate) that includes a mineral (e.g., calcium, zinc, etc.) and the beta-hydroxybutyrate compound coupled to another compound.
  • the beta-hydroxybutyrate may include single isomer beta- hydroxybutyrate and/or polymer beta-hydroxybutyrate.
  • R-beta- hydroxybutyrate may include single isomer R-beta-hydroxybutyrate and/or polymer R-beta- hydroxybutyrate.
  • beta-hydroxybutyrate may be administered with 1,3-butanediol, ethyl acetoacetate, ethyl beta-hydroxybutyrate.
  • the beta-hydroxybutyrate may include racemic mixtures and/or individual isomers of betahydroxy -butyrate. In some implementations, one or more specific chiralities of beta- hydroxybutyrate may be utilized. For example, R-beta-hydroxybutyrate (also referred to as D-beta-hydroxybutyrate), S-beta-hydroxybutyrate (also referred to as L-beta- hydroxybutyrate), and/or mixtures (e.g., raecemic mixtures) thereof may be utilized.
  • R-beta-hydroxybutyrate also referred to as D-beta-hydroxybutyrate
  • S-beta-hydroxybutyrate also referred to as L-beta- hydroxybutyrate
  • mixtures e.g., raecemic mixtures
  • R-beta-hydroxybutyrate may be included in the composition (e.g., a more purified form of R-beta-hydroxybutyrate rather than D, L-beta-hydroxybutyrate).
  • R-beta-hydroxybutyrate may include less than approximately 10 percent, less than approximately 5 percent, or less than approximately 1 percent L-beta-hydroxybutyrate.
  • R- beta-hydroxybutyrate may have a greater bioavailability than other chiralities of beta- hydroxybutyrate.
  • R-beta-hydroxybutyrate may have a greater impact on a health of an individual (e.g., due to decreased side effects; increase ketone levels, weight loss, mental acuity, fat loss, etc.) than L-beta-hydroxybutyrate and/or D,L-beta-hydroxybutyrate.
  • R-beta-hydroxybutyrate may cause improvements in health not capable by L-beta-hydroxybutyrate and/or D, L-beta-hydroxybutyrate.
  • R-beta- hydroxybutyrate may have less impurities due to manufacturing, such as less crotonic acid (e.g., which can be harmful to individuals), than other forms of beta-hydroxybutyrate (e.g., L-beta-hydroxybutyrate and/or D, L-beta-hydroxybutyrate).
  • R- beta-hydroxybutyrate may be more capable of binding with other compounds (e.g., purine, lysine, potassium, and/or other amino acids; dihydroberberine; etc.) to deliver the beta- hydroxybutyrate to a human.
  • R-beta-hydroxybutyrate e.g., greater than 90 percent purity of R-beta-hydroxybutyrate and less than 10 percent L-beta-hydroxybutyrate
  • mixtures with R-beta-hydroxybutyrate may be administered to humans.
  • a smaller amount of R-beta-hydroxybutyrate may be as pharmaceutically effective (e.g., in increasing and/or maintaining weight loss; in increasing and/or maintaining elevated ketone levels, etc.) or more pharmaceutically effective as D,L- beta-hydroxybutyrate (e.g., raecemic mixture of D- and L-beta-hydroxybutyrate).
  • R-beta-hydroxybutyrate may be administered to achieve the approximately the same efficacy as D, L-beta-hydroxybutyrate and/or L-beta- hydroxybutyrate.
  • the R-beta-hydroxybutyrate may be more bioavailable than other chiralities of beta-hydroxybutyrate and thus allow a smaller effective amount than other chiralities.
  • the administration amount of beta- hydroxybutyrate to be reduced (e.g., when compared to the administration amount of D,L- beta-hydroxybutyrate) while providing a pharmaceutically effective amount, such as (e.g., for weight loss and/or maintenance; for elevating and/or maintaining blood ketone levels).
  • a pharmaceutically effective amount such as (e.g., for weight loss and/or maintenance; for elevating and/or maintaining blood ketone levels).
  • Reducing the amount of beta-hydroxybutyrate, when the beta-hydroxybutyrate is provided in salt form may reduce a user’s intake of the cation of the salt (e.g., sodium, potassium, etc.).
  • beta-hydroxybutyrate salts such as sodium, potassium, magnesium, and calcium
  • reducing the amount of beta-hydroxybutyrate salt by using R-beta- hydroxybutyrate may inhibit side effects and/or health problems associated salts combined with beta-hydroxybutyrate administration in users.
  • a pharmaceutically effective amount of R-beta- hydroxybutyrate may be administered in an individual to promote and/or maintain ketosis, cause weight loss and/or manage weight, and/or increase blood ketone levels.
  • R-beta-hydroxybutyrate may be administered to an individual.
  • approximately 0.1 g to approximately 15 g of R-beta-hydroxybutyrate may be administered to an individual.
  • approximately 5 g to approximately 15 g of R-beta-hydroxybutyrate may be administered to an individual.
  • approximately 1 g to approximately 10 g of betahydroxybutyrate may be administered, for example, once a day to 5 times a day (e.g., to administer up to 50 g of beta-hydroxybutyrate).
  • the administration may cause weight loss and/or maintenance; elevated beta-hydroxybutyrate levels in the blood; elevated, reduced, and/or maintenance of blood ketone levels; induction and/or maintenance of ketosis; and/or reduction; improve mental acuity; improve focus; improve energy; improve cognitive function; reduce traumatic brain injury; improve diabetes; improve gluocose tolerance; decrease blood glucose levels; reduce neurological disorders and/or symptoms thereof; improve cancer and/or symptoms thereof; improve inflammatory conditions; suppressing appetite; improve symptoms associated with aging; provide anti-glycation affects; improve epilepsy and/or symptoms thereof; improve depression and/or symptoms thereof; improve performance; improve strength; increase muscle mass; increase fat loss; improve body composition; improve energy; improve focus; improve cognitive function; improve mood and/or well-being; and/or combinations thereof.
  • the beta-hydroxybutyrate e.g., R-beta- hydroxybutyrate
  • the beta-hydroxybutyrate may be administered in healthy and not healthy individuals (e.g., individuals with diseases and/or
  • the beta-hydroxybutyrate such as R-beta- hydroxybutyrate
  • a compound such as an amino acid.
  • beta-hydroxybutyrate may be coupled to (e.g., chemically bonded to) amino acids, such as leucine, lysine, arginine, histidine, ornithine, creatine, agmatine, citrulline and/or combinations thereof.
  • R-beta-hydroxybutyrate may be utilized rather than other chiralities since R-beta-hydroxybutyrate may be more easily bound to leucine, purine, lysine, and/or other amino acids.
  • beta- hydroxybutyrate that is coupled to an amino acid may reduce the intake of cations associated with beta-hydroxybutyrate salts (e.g., which may inhibit side effects associated with administration) and/or allow administration of another compound that has health benefits (e.g., administration of some amino acid may promote smooth muscle growth and/or cell repair).
  • approximately 0.5 g to approximately 10 g of amino acid may be administered with a beta-hydroxybutyrate.
  • less than approximately 50 g of R-beta-hydroxybutyrate and less than approximately 60 mg of an amino acid, such as leucine, may be administered daily.
  • approximately 0.5 g to approximately 2 g of an amino acid, such as leucine may be administered with a beta-hydroxybutyrate.
  • approximately the composition administered may include approximately 0.1 to approximately 7 g R-beta-hydroxybutyrate and approximately 1-3 g of leucine.
  • the R-beta-hydroxybutyrate and the leucine may be a mixture; administered separately and proximate in timing; a complex, and/or administered in any other appropriate manner.
  • the composition may include R-beta-hydroxybutyrate salt and beta-hydroxybutyrate - amino acid complex (e.g., beta-hydroxybutyrate bound to amino acid, such as R-beta-hydroxybutyrate - leucine complex).
  • R-beta-hydroxybutyrate salt and beta-hydroxybutyrate - amino acid complex e.g., beta-hydroxybutyrate bound to amino acid, such as R-beta-hydroxybutyrate - leucine complex.
  • an individual may be administered a first weight amount of sodium beta-hydroxybutyrate and a second weight amount of beta-hydroxybutyrate amino-acid complex. The first amount and the second amount may be different or the same.
  • the beta-hydroxybutyrate composition may include beta- hydroxybutyrate salt and beta-hydroxybutyrate esters.
  • an individual may be administered a first weight amount of sodium beta-hydroxybutyrate and a second weight amount of beta-hydroxybutyrate ester. The first amount and the second amount may be different or the same.
  • the beta-hydroxybutyrate salt and the beta-hydroxybutyrate ester may be a bound complex, a mixture of compounds, and/or separately administered approximately concurrently.
  • the beta-hydroxybutyrate ester may be in powdered form (e.g., plated beta-hydroxybutyrate ester), liquid and/or gel form.
  • beta-hydroxybutyrate salt and beta-hydroxybutyrate ester during administration may allow less salt to be utilized while producing a result (e.g., weight maintenance and/or loss; enhanced and/or maintained ketosis; elevated blood ketone levels; blood glucose reduction and/or maintenance; increase in energy; increase in mood; increase in performance; and/or increase in cognitive function).
  • elevated ketone levels e.g., elevated blood ketone levels
  • the administration of the first amount of beta-hydroxybutyrate salt may cause a first level of blood ketone level, which may be maintained by processing of the second amount of the beta-hydroxybutyrate ester (e.g., as the body of the individual processes the beta-hydroxybutyrate ester the level of beta- hydroxybutyrate in the blood, and thus blood ketone level, may also increase over time to enhance and/or maintain the initial elevation caused by of the administered beta- hydroxybutyrate salt.).
  • a ratio of beta-hydroxybutyrate to beta- hydroxybutyrate ester may be approximately 1 beta-hydroxybutyrate salt: approximately 1 beta-hydroxybutyrate ester to approximately 1 beta-hydroxybutyrate salt: approximately 20 beta-hydroxybutyrate ester.
  • the ratio of beta-hydroxybutyrate to beta-hydroxybutyrate ester may be approximately 20 beta-hydroxybutyrate salt: approximately 1 beta- hydroxybutyrate ester to approximately 1 beta-hydroxybutyrate salt: approximately 20 beta- hydroxybutyrate ester.
  • a ratio of beta-hydroxybutyrate to beta- hydroxybutyrate ester may be approximately 1 beta-hydroxybutyrate salt: approximately 1 beta-hydroxybutyrate ester to approximately 1 beta-hydroxybutyrate salt: approximately 5 beta-hydroxybutyrate ester.
  • beta-hydroxybutyrate esters derived from alcohols, such as altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, glycerol, gulose, idose, lactose, lyxose, mannose, ribitol, ribose, ribulose, sucrose, talose, threose, xylitol, xylose, galactosamine, glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol, threitol, (S)-l,2- propanediol and/or (R)- 1,3 -
  • a derivative of the beta- hydroxybutyrate may include structures of (R)-3-hydroxybutyric acid and an exemplary ester thereof (a glycerol monoester).
  • the R chirality of the derivatives may be selected for inclusion in the composition in some implementations (e.g., to deliver R-beta- hydroxybutyrate with the administration of the compound).
  • butyrate, beta-hydroxybutyrate e.g., R-beta- hydroxybutyrate
  • related compounds e.g., R-beta- hydroxybutyrate
  • additional compounds may or may not be capable of independently increasing ketone levels, maintaining ketone levels, inducing ketosis, and/or maintaining ketosis.
  • additional compounds capable of independently increasing blood ketone levels may include short chain fatty acids (e.g., fatty acid with between 2 carbons than 6 carbons), short chain triglycerides (e.g., triglycerides with less than 6 carbons), medium chain fatty acids (e.g., fatty acid with 6-12 carbons), medium chain triglycerides (e.g., triglycerides with 7-12 carbons), long chain fatty acids (e.g., fatty acids with more than 12 carbons), long chain triglycerides (e.g., triglycerides with more than 12 carbons), and/or combinations thereof.
  • short chain fatty acids e.g., fatty acid with between 2 carbons than 6 carbons
  • short chain triglycerides e.g., triglycerides with less than 6 carbons
  • medium chain fatty acids e.g., fatty acid with 6-12 carbons
  • medium chain triglycerides e.g.,
  • short chain fatty acids and/or triglycerides may include acetate, propionate, and/or butyrate.
  • Medium chain fatty acids and/or triglycerides may include lauric acid and/or coconut oil, coconut milk powder, fractionated coconut oil, isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid, ethoxylated triglyceride, triglyceride derivatives thereof, aldehyde triglyceride derivatives thereof, monoglyceride derivatives thereof, diglyceride derivatives thereof, triglyceride derivatives thereof, and/or alkyl esters thereof.
  • Long chain fatty acids and/or triglycerides may include dairy products and/or palm oil.
  • a compound including R-beta-hydroxybutyrate and an additional compound that is independently capable of increasing ketone levels may increase ketone levels greater than merely the capability of each component individually (e.g., greater than an additive increase).
  • a pharmaceutically effective amount of one or more short chain fatty acids and/or one or more short chain triglycerides may be administered with a pharmaceutically effective amount of beta-hydroxybutyrate.
  • approximately 1 g to approximately 10 g of beta-hydroxybutyrate and approximately .1 g to approximately 50 g of short chain fatty acid and/or triglyceride may be administered from once a day to approximately 5 times a day.
  • approximately 1 g to approximately 3 g of beta-hydroxybutyrate and approximately 1 g of short chain fatty acid and/or triglyceride may be administered from once a day to approximately 5 times a day.
  • the short chain fatty acid and/or triglyceride may include butyrate or derivatives of butyrate.
  • Butyrate and/or derivatives of butyrate may be administered with and/or without beta-hydroxybutyrate to manage metabolic conditions, such as ketosis, and/or for other appropriate therapeutic purposes.
  • Administered butyrate may be converted to beta-hydroxybutyrate in humans, and thus may increase the amount of beta-hydroxybutyrate delivered to the user.
  • administration of butyrate and beta-hydroxybutyrate may promote hGH synthesis, improve basal and GHRH-induced hGH- secretion, increase muscle fiber cross- sectional area, inhibit intramuscular fat accumulation; reduce fat mass in a user; improve glucose metabolism; increase markers of mitochondrial biogenesis in skeletal muscle and/or whole-body oxygen consumption; reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity; cause butyrate enhanced intracellular free cytosolic calcium levels (e.g., by acting through GPR41 and 43); increase beta-hydroxybutyrate levels; and/or support barrier function(s) in the gut and/or reduce inflammation associated with ulcerative colitis.
  • beta-hydroxybutyrate Since butyrate is processed by the body to provide beta- hydroxybutyrate, the delivery of beta-hydroxybutyrate via the butyrate may supplement the directly administered beta-hydroxybutyrate to maintain a level of beta-hydroxybutyrate in the blood (e.g., to promote ketosis, weight loss and/or management, etc.).
  • butyrate and/or butyric acid may not be palatable to individuals (e.g., since the odor and taste are often compared to vomit).
  • butyrate and/or beta-hydroxybutyrate e.g., R-beta-hydroxybutyrate
  • the butyrate and/or beta-hydroxybutyrate may be encapsulated, microemulsion, liposomes, agglomeration, masking/flavoring technologies, and/or otherwise processed as appropriate to reduce organoleptic reactions from individuals administered the described composition(s).
  • microencapsulated butyrate, beta-hydroxybutyrate, and/or butyric acid may be utilized (e.g., in combination with beta-hydroxybutyrate).
  • Using microencapsulated butyrate, beta-hydroxybutyrate, and/or butyric acid may increase individual satisfaction and/or compliance with an administration schedule since odor from the butyrate and/or butyric acid may be reduced and/or removed.
  • the microencapsulated butyrate, beta-hydroxybutyrate, and/or butyric acid may be a free flowing granular powder; dispersible in water; stable in acidic water solution for 30 minutes; allow controlled release in stomach and/or small intestines; inhibit glucose response (e.g., to any added materials); and/or allow delivery of a high butyrate content (e.g., around 70%).
  • a pharmaceutically effective amount of butyrate may be administered via triglyceride tributyrin (e.g., glyceryl tributyrate or tributyrin).
  • the butyrate via triglyceride tributyrin may be administered separately and/or in conjunction with one or more of the other described compounds (e.g., beta-hydroxybutyrate, fatty acids and/or esters, etc.). For example, up to approximately 200 mg/kg of the individual may be administered (e.g., up to 3 times daily). Administration of the tributyrin may allow a delayed release of butyrate to the body as the tributyrin is processed by the body of the individual.
  • the tributyrin may be unencapsulated and/or encapsulated (e.g., mi croencap sul ated) .
  • administration of beta-hydroxybutyrate and a short chain compound may unexpectedly increase beta-hydroxybutyrate concentrations in the blood more than the administration of similar amounts of beta-hydroxybutyrate and medium chain compounds (e.g., short chain fatty acid and/or short chain triglyceride) and/or may increase beta-hydroxybutyrate concentrations in the blood more than each component individually.
  • a short chain compound e.g., short chain fatty acid and/or short chain triglyceride
  • medium chain compounds e.g., short chain fatty acid and/or short chain triglyceride
  • a pharmaceutically effective amount of beta- hydroxybutyrate may be administered with a pharmaceutically effective amount of long chain fatty acid and/or triglyceride.
  • 0.1-50 g of beta-hydroxybutyrate and 0.1 to 50 g of long chain fatty acid may be administered to an individual between 1-5 times a day.
  • approximately 1 g to approximately 3 g of beta- hydroxybutyrate and approximately 1 g of long chain fatty acid and/or triglyceride may be administered from once a day to approximately 5 times a day.
  • beta-hydroxybutyrate, short chain compound(s) e.g., fatty acids and/or triglycerides, butyrate
  • medium chain compound(s) e.g., fatty acids and/or triglycerides
  • beta-hydroxybutyrate, short chain compound(s) e.g., fatty acids and/or triglycerides, butyrate
  • medium chain compound(s) e.g., fatty acids and/or triglycerides
  • approximately 0.1g to approximately 50 g beta- hydroxybutyrate, approximately 0.1g to approximately 50 g short chain triglyceride, and approximately 0.1g to approximately 50 g medium chain fatty acid such as lauric acid and/or coconut oil may be administered between 1-5 times a day.
  • approximately 1 g to approximately 3 g of beta-hydroxybutyrate and approximately 1 g of short chain fatty acid and/or triglyceride and/or approximately 1 g of medium chain fatty acid and/or triglyceride may be administered from once a day to approximately 5 times a day.
  • approximately 0.1g to approximately 20g betahydroxybutyrate e.g., salts, esters, isomers, and/or other appropriate forms
  • approximately 0.1g to approximately 20g butyrate may be administered in humans.
  • beta-hydroxybutyrate such as berberine and/or associated metabolites (e.g., dihydroberberine and/or tetrahydroberberine).
  • berberine and/or associated metabolites e.g., dihydroberberine and/or tetrahydroberberine.
  • U.S. Patent Application No. entitled “ADMINISTRATION OF DIH DROBERBERINE” to Lowery et al, filed April 19, 2017 and U.S. Provisional Patent Application No. 62/324,794, entitled “ADMINISTRATION OF DH4YDROBERBERINE” to Lowery et al, filed April 19, 2016, describe dihydroberberine administration with ketone sensitizers such as beta-hydroxybutyrate, and is hereby fully incorporated herein.
  • one or more beta-hydroxybutyrates and/or other compounds described herein may be utilized as a ketone sensitizer with the dihydroberberine.
  • directly administering beta-hydroxybutyrate plus another compound that is processed to deliver beta-hydroxybutyrate may allow a first level of beta-hydroxybutyrate in the blood to be maintained over a period of time.
  • beta-hydroxybutyrate may elevate blood beta-hydroxybutyrate levels to a first concentration and this concentration may be approximately maintained over a period of time by providing additional beta-hydroxybutyrate via another compound administered approximately concurrently (e.g., short chain fatty acid and/or triglyceride, beta-hydroxybutyrate ester, beta-hydroxybutyrate polymer, beta-hydroxybutyrate amino acid complex, etc.).
  • another compound administered approximately concurrently e.g., short chain fatty acid and/or triglyceride, beta-hydroxybutyrate ester, beta-hydroxybutyrate polymer, beta-hydroxybutyrate amino acid complex, etc.
  • one or more other compounds may be administered (e.g., included in the composition and/or separately administered) with the butyrate (e.g., microencapsulated butyrate), beta-hydroxybutyrate (e.g., R-beta-hydroxybutyrate) and/or fatty acids or esters, such as short chain fatty acids.
  • the butyrate e.g., microencapsulated butyrate
  • beta-hydroxybutyrate e.g., R-beta-hydroxybutyrate
  • fatty acids or esters such as short chain fatty acids.
  • compositions may include, but are not limited to amino acids, amino acid metabolites, vitamins, minerals, coconut milk powder, flavorings, colorings, binders, electrolytes, tetrahydrobiopeterin, nucleic acids, alpha-ketoglutaric acid, alpha lipoic acid, nutritional co-factors, beta-methyl-beta- hydroxybutyrate, arginine alpha-ketoglutarate, R-alpha lipoic acid, thiamine, NAD+, NADH, riboflavin, FAD+, FADH, riboflavin-5-phosphate, niacin, nicotinic acid, niacinamide, inositol hexanicotinate, pyridoxine, pyridoxal, pyridoxamine, ascorbic acid and ascorbate salts, citric acid, malic acid, sodium benzoate, Pyridoxal-5-Phosphate, methylcobalamin, cyanocobalamin,
  • administration of a composition that includes betahydroxybutyrate may improve the health of an individual.
  • R-beta-hydroxybutyrate may be capable of providing a greater impact on the health of an individual than D,L-beta- hydroxybutyrate and/or L-beta-hydroxybutyrate.
  • L-beta- hydroxybutyrate may decrease the effectiveness of R-beta-hydroxybutyrate with respect to at least a portion of the impact on health. With respect to some impacts on health, L-beta- hydroxybutyrate may have no impact on health.
  • L-beta-hydroxybutyrate may not achieve some of the same results (e.g., in health improvement) as R-beta-hydroxybutyrate.
  • unexpectedly administration of D, L-beta-hydroxybutyrate rather than R-beta-hydroxybutyrate may not have the same impact on health and/or have less of an impact on health of an individual.
  • administration of a composition that includes R-beta-hydroxybutyrate may improve and/or maintain an individual’s health.
  • R-beta-hydroxybutyrate as described may increase lifespan in individuals following a dietary plan (e.g., standard American low-fat, ketogenic, Paleo, Mediterranean, etc.) and/or not following a dietary plan. For example, approximately 10 g of R-beta-hydroxybutyrate to approximately 30 g R-beta-hydroxybutyrate may be administered to increase lifespan. In some implementations, other appropriate amounts of R-beta-hydroxybutyrate may be included in the composition. [097] In some implementations, administration of R-beta-hydroxybutyrate may treat and/or lesson the impact of symptoms of disease(s) and/or disorders, such as diseases that impact cognitive function.
  • a dietary plan e.g., standard American low-fat, ketogenic, Paleo, Mediterranean, etc.
  • administration of R-beta-hydroxybutyrate may treat and/or lesson the impact of symptoms of disease(s) and/or disorders, such as diseases that impact cognitive function.
  • R-beta-hydroxybutyrate may increase motor function in individuals with Parkinson’s disease. For example, approximately 5 g of R- beta-hydroxybutyrate to approximately 15 g R-beta-hydroxybutyrate may be administered to increase motor function. In some implementations, other appropriate amounts of R-beta- hydroxybutyrate may be included in the composition.
  • R-beta-hydroxybutyrate may increase fat loss. Unlike with conventional diets, in which weight loss often comes from decreases in water retention and/or muscle mass, administration of R-beta-hydroxybutyrate may cause decreases in fat loss (see for example, Figure 9B). In addition, administration of R-beta-hydroxybutyrate may decrease levels of LPL in the body, and thus reduce or inhibit fat storage and/or encourage existing fat storage utilization by the body. For example, approximately 1 g of R- beta-hydroxybutyrate to approximately 20 g R-beta-hydroxybutyrate may be administered to cause fat loss and/or reduce fat storage. In some implementations, other appropriate amounts of R-beta-hydroxybutyrate may be included in the composition. Administration of R-beta-hydroxybutyrate may allow fat loss greater than 5 kg while maintaining lean mass. In some implementations, the administration of R-beta-hydroxybutyrate increases the amount of fat used as fuel.
  • administration of R-beta-hydroxybutyrate may improve and/or maintain health markers such as C-reactive protein and/or fasting glucose.
  • Administration of R-beta-hydroxybutyrate may decrease inflammation (e.g., as shown by C-reactive protein levels).
  • Administration of R-beta-hydroxybutyrate may decrease fasting glucose.
  • approximately 3 g of R-beta-hydroxybutyrate to approximately 20 g R-beta-hydroxybutyrate may be administered to cause a reduction in and/or maintain a low fasting glucose.
  • other appropriate amounts of R-beta- hydroxybutyrate may be included in the composition.
  • R-beta- hydroxybutyrate may be administered with one or more other compounds to decrease glucose levels and/or sensitivity.
  • administration of a composition of R-beta- hydroxybutyrate and a berberine, such as dihydroberberine may cause reduce and/or maintain low fasting glucose.
  • Administration of a composition of R-beta-hydroxybutyrate and a berberine, such as dihydroberberine may cause reduce and/or maintain low glucose levels.
  • less than approximately 15 g of R-beta-hydroxybutyrate may be administered with less than approximately 600 mg of dihydroberberine.
  • R-beta-hydroxybutyrate may decrease ketone levels (see e.g., Figures 11 A and 1 IB). Decreasing blood ketone levels may increase weight loss, maintain weight loss, improve performance, increase mental acuity, and/or have other health improvement and health maintenance features. For example, even at levels less than 10 g (e.g., approximately 5 g), administration of R-beta-hydroxybutyrate may decrease ketone levels while L-R-beta-hydroxybutyrate does not, and D,L-beta-hydroxybutyrate does not to the same extent.
  • R-beta-hydroxybutyrate may increase blood ketone levels 5 times as much as similar administration amounts of D,L-beta-hydroxybutyrate.
  • an amount of R-beta-hydroxybutyrate e.g., when compared with administering D,L-beta- hydroxybutyrate
  • a decrease in an amount cation e.g., sodium, potassium, etc. may also be administered.
  • R-beta-hydroxybutyrate may allow administration to more people, increase user satisfaction, and/or decrease side effects (e.g., associated with additional consumption of these cations).
  • approximately 0.1 g of R-beta- hydroxybutyrate to approximately 10 g R-beta-hydroxybutyrate may be administered to increase blood ketone levels.
  • approximately 0.5 g of R-beta-hydroxybutyrate to approximately 3 g R-beta-hydroxybutyrate may be administered to maintain blood ketone levels.
  • other appropriate amounts of R-beta-hydroxybutyrate may be included in the composition.
  • R-beta-hydroxybutyrate may increase performance and decrease perceived exertion (e.g., as opposed to when administered D,L-beta-hydroxybutyrate). For example, approximately 3 g of R-beta-hydroxybutyrate to approximately 15 g R-beta- hydroxybutyrate may be administered to increase performance and/or decrease perceived exertion. Approximately 5 g of R-beta-hydroxybutyrate to approximately 15 g R-beta- hydroxybutyrate may be administered to increase performance and/or decrease perceived exertion. In some implementations, other appropriate amounts of R-beta-hydroxybutyrate may be included in the composition.
  • oral administration of R-beta-hydroxybutyrate may increase muscle protein synthesis while D,L-beta-hydroxybutyrate does not increase muscle protein synthesis.
  • approximately 10 g of R-beta-hydroxybutyrate to approximately 30 g R-beta-hydroxybutyrate may be administered to increase muscle protein synthesis.
  • Approximately 5 g of R-beta-hydroxybutyrate to approximately 15 g R-beta- hydroxybutyrate may be administered, in some implementations, to increase muscle protein synthesis.
  • other appropriate amounts of R-beta-hydroxybutyrate may be included in the composition.
  • the administration of R-beta-hydroxybutyrate may decrease perceived hunger and/or increase satiety) which may inhibit overeating and thus promote weight loss (see e.g., Figures 13A and 13B).
  • the administration of R-beta-hydroxybutyrate, unlike D,L-beta- hydroxybutyrate may increased perceived energy (see e.g., Figures 13C).
  • administering increased mental acuity. For example, approximately 0.1 g of R-beta-hydroxybutyrate to approximately 10 g R-beta-hydroxybutyrate may be administered to increase mental acuity. Approximately 5 g of R-beta-hydroxybutyrate to approximately 15 g R-beta- hydroxybutyrate may be administered to increase mental acuity. In some implementations, other appropriate amounts of R-beta-hydroxybutyrate may be included in the composition.
  • R-beta-hydroxybutyrate may be supplemented with other forms of beta-hydroxybutyrate, butyric acid, and/or butyrate.
  • the composition administered may include R-beta- hydroxybutyrate.
  • the amount of R-beta-hydroxybutyrate included in the composition may be selected to obtain a result (e.g., induce ketosis; maintain ketosis; increase ketone levels, mental acuity, strength, etc.) upon administration (e.g., a pharmaceutically effective amount may be administered at a dosage and/or over a predetermined time period).
  • the dosage and/or frequency of dosage may vary over time (e.g., initial vs a lower dosage for maintenance, vary based on time of day, vary based on whether taken with or without a meal, etc.).
  • the R-beta-hydroxybutyrate in the composition may include any appropriate and/or appropriate number of forms, such as salts, derivatives (e.g., esters), polymers, and/or complexes with other compounds.
  • the composition may include R-beta- hydroxybutyrate salt (e.g., sodium R-beta-hydroxybutyrate, magnesium R-beta- hydroxybutyrate, and/or potassium R-beta-hydroxybutyrate) and/or another form of R-beta- hydroxybutyrate (e.g., ester, polymer, complex, etc.).
  • the composition may include an ester of R-beta-hydroxybutyrate.
  • the composition may include an amino acid (e.g., separate and/or complexed with R-beta-hydroxybutyrate), such as leucine.
  • an amino acid e.g., separate and/or complexed with R-beta-hydroxybutyrate
  • leucine an amino acid
  • the use of non-salt base R-beta-hydroxybutyrate may increase user satisfaction (e.g., by reducing the cation, such as sodium and/or potassium, load due to ingestion of the composition; by decreasing side effects; etc.), increase the applicability of the administration (e.g., since users sensitive to the cations of the R-beta-hydroxybutyrate salts may be less sensitive to the non-salt and/or lower salt plus non-salt forms of the composition).
  • the administration of the composition may increase blood ketone levels, induce ketosis, maintain blood ketone levels, maintain ketosis, increase health, increase strength, increase mental acuity, etc.
  • a first composition that includes R-beta-hydroxybutyrate salt may be administered to cause a first impact (e.g., induce ketosis, quickly increase mental acuity, quickly increase strength, etc.) and a second composition that includes non-salts R-beta-hydroxybutyrate (e.g., esters, polymers, complexes, etc.) and/or lower levels of R-beta-hydroxybutyrate salt may be utilized to cause a second impact (e.g., maintain ketosis, maintain mental acuity, maintain increased strength, etc.).
  • the form(s) of R-beta-hydroxybutyrate included in the may be selected based on the delivery form.
  • the composition may include R-beta-hydroxybutyrate polymer (e.g., due to taste since increased cations like sodium may decrease palatability; due to nutrition since increased cations such as sodium may decrease nutrition; due to mixability, etc.).
  • the composition may include R-beta-hydroxybutyrate salts or other forms (e.g., microencapsulated) to provide quick dissolve powders.
  • a composition may include R-beta-hydroxybutyrate.
  • the R-beta-hydroxybutyrate may be in any appropriate form (e.g., salt, ester, polymer, complex, derivatives thereof, and/or combinations thereof).
  • the composition may include one or more additional compositions. Additional composition(s) may be capable of independently increasing blood ketone levels (e.g., fatty acids or esters, berberine or berberine metabolites such as dihydroberberine, etc.). Additional composition(s) may be capable of independently decreasing blood glucose levels (e.g., berberine or berberine metabolites such as dihydroberberine).
  • additional compounds may not be capable of independently increasing blood ketone levels and/or decreasing blood glucose levels (e.g., additives, flavorings, colorings, minerals, vitamins, binders, anti-caking agents, etc.).
  • the composition may be administered in an effective amount to cause a predetermined health impact (e.g., predetermined level of ketosis, blood ketone level, mental acuity, strength increase, perceived energy, fat loss, weight loss, etc.).
  • the composition may be administered to an individual in a predetermined amount and/or different amounts over an administration schedule.
  • a first criteria e.g., period of time, number of doses, predetermined health impact
  • the dosage amount may be altered.
  • first dose(s) of the composition may be administered to cause a predetermined health impact and additional lower dose(s) of the composition may be administered to maintain the predetermined health impact (e.g., caused in part by the first doses).
  • the composition may be administered in any appropriate delivery form (e.g., tablet; capsule; food products such as powdered products that can be mixed into food, mixed into beverages, and/or consumed directly; beverage product; etc.).
  • the composition may be administered according to any appropriate schedule (e.g., periodic dosages, dosages as user desires, etc.).
  • the administration schedule may inhibit administration that elevates blood ketone levels too high, decreases blood glucose levels too low, and/or causes an individual to consume a dosage that substantially elevates the risk of adverse and/or side effects, in some implementations.
  • the composition may include a long acting component and/or be long-acting.
  • the delivery of R-beta-hydroxybutyrate may be slower than a digestion of a beta-hydroxybutyrate salt (e.g., R-beta-hydroxybutyrate salt).
  • the composition may include a R-beta-hydroxybutyrate and a long acting R-beta-hydroxybutyrate form (e.g., polymer, ester, coated and/or processed form to provide slow release).
  • a first dose(s) may include at least one non-long acting form of beta-hydroxybutyrate and a second dose(s) may include at least one long-acting form of beta-hydroxybutyrate.
  • the first dose(s) may be administered to cause a predetermined health impact and the second dose(s) may be administered to maintain the caused predetermined health impact.
  • users may select the appropriate dose based on user preference and/or properties (e.g., a user on a ketogenic diet may chose the second dose since the user may already be in ketosis).
  • Example 1 As in Example 1, five subjects were subject to three separate glucose challenge tests (75g glucose) after administration of 500 mg berberine (BB), 250 mg of dihydroberberine (DHBB) or 500 dihydroberberine.
  • Figure 2 illustrates a ranking which compositions caused the lowest blood glucose levels during a oral glucose challenge.
  • 250 mg of DHBB may control blood glucose levels better than even 500 mg of DHBB.
  • individuals e.g., individuals with moderate glucose tolerance
  • dihydroberberine administration resulted in lower blood glucose than administration of berberine in most individuals.
  • a subject was subject to a glucose challenge test (75g glucose) after administration of 250 mg dihydroberberine (DHBB) and a glucose challenge test after administration of 250 mg dihydroberberine (DHBB) along with 5 mg of beta-hydroxybutyrate (e.g., 5 mg sodium beta-hydroxybutyrate).
  • DHBB glucose challenge test
  • beta-hydroxybutyrate e.g., 5 mg sodium beta-hydroxybutyrate
  • EXAMPLE 5 [0124] 4 subjects were administered 10 mg of sodium D,L-beta-hydroxybutyrate and their blood ketone level in mmol/dL was tested after administration, 30 minutes, 60 minutes, 90 minutes, 120 minutes, and 180 minutes after administration. Each subject was also subsequently studied after administration of 10 g of sodium R-beta-hydroxybutyrate and 5 g of sodium R-beta-hydroxybutyrate. As illustrated in Figure 5, on average, administration of 5 mg of sodium R-beta-hydroxybutyrate produced approximately the same blood ketone level in a subject after 30 minutes, 60 minutes, 90 minutes, 120 minutes, and 180 minutes as 10 g of D,L-beta-hydroxybutyrate.
  • FIG. 6 illustrates an average blood ketone concentration (mmol/L) for the subjects after administration, after 30 minutes, after 60 minutes, after 90 minutes, after 120 minutes, and after 180 minutes.
  • administering caused greater elevation of blood ketone levels than administration of a similar amount of medium chain compound (illustrated in the blue bars or first bar in each set) at least after administration, after 30, 60, 90 minutes, and 180 minutes.
  • a short chain compound illustrated in red bars or the second bar in each set
  • medium chain compound illustrated in the blue bars or first bar in each set
  • short chain compounds e.g., fatty acids and/or triglycerides
  • medium chain compounds e.g., fatty acids and/or triglycerides
  • administration of short chain compounds may unexpectedly allow a smaller weight amount, when compared to medium chain compounds, to be administered to produce the same result (e.g., blood ketone level, weight loss, weight management, etc.) and/or allow greater results (e.g., when compared with similar amount of medium chain compounds).
  • the supplementation of rats diets with R-beta-hydroxybutyrate increased lifespan for approximately in at least approximately 38.5% of the rats. Since the rat study was performed as an approximation of impact in humans, the addition of R-beta- hydroxybutyrate to a standard American low-fat diet may increase lifespan.
  • Figure 8 illustrates chart illustrating the results of the motor skill testing following an example implementation of administration of R-beta-hydroxybutyrate.
  • Figure 8 illustrates average results for a similar non-Parkinson’s population, the patient preadministration of R-beta-hydroxybutyrate, and the patient post-administration of R-beta- hydroxybutyrate.
  • the administration of R-beta-hydroxybutyrate increased motor function (e.g., approximately 30 minutes after administration of the R-beta- hydroxybutyrate).
  • FIG. 9 A illustrates a chart that shows the results after 3 months of administration. As illustrated, the individual experienced a greater than approximately 10% decrease in fat mass.
  • Figure 9B illustrates that the fat loss was sustained while maintaining lean mass.
  • the R-beta-hydroxybutyrate may cause weight loss through fat loss rather than lean mass (e.g., muscle mass).
  • a first grouping of 10 rats were given a standard diet
  • a second grouping of 10 rats were given a ketogenic diet
  • a third grouping of 10 rats were on the standard diet but given a first dosage of R-beta- hydroxybutyrate salt (e.g., equivalent to 5 g)
  • a fourth grouping was on the standard iet but given a second dosage of R-beta-hydroxybutyrate salt (e.g., equivalent to 10 g).
  • Figure 10 illustrates the average Lipoprotien lipase (LPL) in the rats.
  • LPL Since LPL is needed to transport fat into adipose tissue, lowering LPL levels would inhibit fat storage and encourage usage of fat storages. As illustrated, supplementation of a standard diet with even lower dosages of R-beta-hydroxybutyrate decreases LPL levels and thus inhibits fat storage.
  • FIG. 13 illustrates the perceived exertion experienced by the individuals. As illustrated, the individuals did not feel an impact in perceived exertion after administration with D,L-beta-hydroxybutyrate as compared with the perceived exertion improvement experienced after administration of R- beta-hydroxybutyrate. Thus, the R-beta-hydroxybutyrate has an unexpectedly impact on ketone levels and performance.
  • R-beta-hydroxybutyrate e.g. 10 g
  • SOD superoxide dismutase 2 levels
  • L-beta-hydroxybutyrate does not decrease blood ketones.
  • D L-beta-hydroxybutyrate does not lower blood ketone levels to the same extent as R-beta-hydroxybutyrate. This indicates that L-beta- hydroxybutyrate may block some of the impact of R-beta-hydroxybutyrate, which is unexpected.
  • RER Respiratory exchange ratio
  • a ratio of 1.0 indicates that 100 % carbohydrate is used as fuel and at 0.7, 100 % fat is used as fuel.
  • R-beta-hydroxybutyrate administration reduces RER approximately 3 x more than D,L-beta-hydroxybutyrate.
  • R-beta- hydroxybutyrate is capable of achieving a result that even more D,L-beta-hydroxybutyrate is unable to (e.g., D,L-beta-hydroxybutyrate increases RER by 17 % rather than decreasing RER).
  • FIG. 13A-13C illustrates the results of the testing.
  • Figure 17A illustrates perceived hunger
  • Figure 17B illustrates perceived satiety
  • Figure 17C illustrates perceived energy.
  • R-beta-hydroxybutyrate improved satiety levels 2.3x better than DL-beta-hydroxybutyrate relative to baseline levels.
  • R-beta-hydroxybutyrate improved perceived energy from 0 to 30 minutes post consumption by double that of D,L-beta-hydroxybutyrate.
  • R-beta- hydroxybutyrate sustained elevated perceived energy levels from 0 minutes at 60, 90, and 120 minutes post consumption, as opposed to D,L-beta-hydroxybutyrate.
  • R- beta-hydroxybutyrate was able to raise perceived energy by 18 % and sustain it for 2 hours post ingestion (e.g., more than 2 times greater than the peak value of increase with the DL- beta-hydroxybutyrate)
  • Figure 14C illustrates the results of the testing (e.g., averages of power measurements). As illustrated, R-beta-hydroxybutyrate administration increased minimum power by 26 %, while the DL-beta-hydroxybutyrate administration raised power by 2 %.
  • Horizontal Tracking testing (e.g., to assess their cognitive function) was performed and administration of D,L-beta-hydroxybutyrate (e.g., 10 g) improved performance by 4.6 %, while the administration of R-beta-hydroxybutyrate (e.g., 10 g) improved performance by 13.8 %, which is approximately 3 times greater improvement.
  • Horizontal Saccades testing was performed (e.g., a saccade is one eye movement and known to become significantly slower if cognitive function declines and improve if cognitive function improves).
  • R-beta-hydroxybutyrate e.g., 5 g
  • the compound for administration was prepared to include an R-beta- hydroxybutyrate amino acid complex.
  • An R-beta-hydroxybutyrate Agmatine complex was prepared and an R-beta-hydroxybutyrate Arginine complex was prepared.
  • Figure 19 illustrates the average blood ketone levels achieved with the R-beta-hydroxybutyrate amino acid complex (e.g., an average of both complexes) when compared with D,L-beta- hydroxybutyrate.
  • blood ketone levels are not only more than double the blood ketone levels achieved with the same quanity of D,L-beta-hydroxybutyrate as R-beta- hydroxybutyrate amino acid complex (e.g., 10 g), but they are more than an additive result of a similar amount of R-beta-hydroxybutyrate and amino acid.
  • Use of the R-beta-hydroxybutyrate amino acid complex may reduce the amount of cation delivered (e.g. since the complex may deliver the R-beta-hydroxybutyrate rather than a R-beta-hydroxybutyrate salt).
  • the reduction of this cation may decrease side effects (e.g., from increased sodium, potassium, and/or magnesium intake), increase user satisfaction, and/or increase the population that can tolerate the administration of R-beta- hydroxybutyrate (e.g., since some individuals may not be capable of increasing loads of these cations due to underlying diseases and/or disorder).
  • R-beta- hydroxybutyrate amino acid complex may also allow a higher yield of R-beta- hydroxybutyrate to be administered (90.8% R-beta-hydroxybutyrate, 5% amino acid) when compared with a similar weight of R-beta-hydroxybutyrate salt (e.g., average of 83% yield for BHB sodium).
  • a composition for administration may include R-beta-hydroxybutyrate and an amino acid, such as Leucine.
  • the R-beta-hydroxybutyrate and leucine maybe complexed and/or mixed together for administration.
  • the R-beta-hydroxybutyrate and leucine may be administered separately but approximately concurrently.
  • Figure 20 illustrates the blood ketone levels after administration of R-beta-hydroxybutyrate (5g) and leucine (2g).
  • the administration of R-beta-hydroxybutyrate and leucine causes greater elevation of blood ketone levels than the administration of R-beta-hydroxybutyrate (5g).
  • the administration of R-beta-hydroxybutyrate and leucine causes greater elevation of blood ketone levels than merely the additive effect of similar quantities of R-beta-hydroxybutyrate and leucine administered separately.
  • a pharmaceutically effective amount of butyrate, betahydroxybutyrate, related compounds, and/or one or more other compounds may be administered to an individual.
  • the pharmaceutically effective amount of the beta-hydroxybutyrate, related compounds, and/or one or more other compounds may be administered to cause weight loss, weight maintenance, elevate blood ketone levels, maintain blood ketone levels, reduce blood glucose levels, maintain blood glucose levels, improve focus, energy, cognitive function, traumatic brain injury, diabetes, neurological disorders, cancer, inflammatory conditions, suppressing appetite, anti-aging, anti-glycation, epilepsy, depression, performance, strength, muscle mass, fat loss, body composition, and/or use as a medicament etc.
  • the pharmaceutically effective amount of butyrate, beta- hydroxybutyrate, related compounds, and/or combinations thereof may be administered to healthy individuals and/or not healthy individuals (e.g., with diseases and/or disorders).
  • the beta- hydroxybutyrate may include the racemic mixture and/or the individual isomers of beta- hydroxybutyrate, such as R-beta-hydroxybutyrate (also known as D-beta-hydroxybutyrate).
  • the beta-hydroxybutyrate may include related compounds.
  • the beta-hydroxybutyrate may be coupled to a compound such as an amino acid.
  • the beta-hydroxybutyrate may include beta-hydroxybutyrate salt and beta-hydroxybutyrate esters, in some implementations.
  • compositions may be administered to induce and/or maintain ketosis.
  • the composition may include approximately 0.5 g to approximately 10 g of R-beta-hydroxybutyrate.
  • Implementations may include one or more of the following features.
  • the amount of the composition administered may include approximately 0.5 to approximately 3 g of R- beta-hydroxybutyrate.
  • the composition may include additional composition, such as compositions that are capable of independently increasing ketone levels, inducing ketosis, and/or maintaining ketosis.
  • the composition may include additional compositions to provide other health benefits (e.g., increase mental acuity, strength, etc.).
  • the composition may include fatty acids and/or esters of fatty acids.
  • the composition may include a short chain fatty acid, an ester of short chain fatty acid, a medium chain fatty acid, an ester of medium chain fatty acid, a long chain fatty acid, or an ester of long chain fatty acid.
  • the composition may include flavoring(s), vitamin(s), mineral(s), and/or binder(s).
  • the composition may be administered up to 5 times daily. The administration of the composition may increase strength, mental acuity, metabolism, fat loss, fat oxidation, motor function, muscle mass, and/or combinations thereof.
  • the 0.5 to 10 g of R-beta- hydroxybutyrate administered includes R-beta-hydroxybutyrate and at least one of a polymer of R-beta-hydroxybutyrate or R-beta-hydroxybutyrate-complex.
  • a composition may include approximately 0.5 g to approximately 10 g of R-beta-hydroxybutyrate and one or more additional compounds capable of maintaining ketosis independently. Administration of the composition may induce and/or maintains ketosis in an individual.
  • Implementations may include one or more of the following features.
  • the R-beta- hydroxybutyrate may include R-beta-hydroxybutyrate salt, R-beta-hydroxybutyrate- amino acid complex, and/or R-beta-hydroxybutyrate polymer.
  • the additional compounds may include fatty acids and/or esters of fatty acids.
  • the fatty acids and/or esters may include natural (e.g., cream, coconut oil, macadamia oil, etc.) and/or artificial fatty acids and/or esters of fatty acids.
  • the composition may include a short chain fatty acid, an ester of short chain fatty acid, a medium chain fatty acid, an ester of medium chain fatty acid, a long chain fatty acid, or an ester of long chain fatty acid.
  • additional compound(s) may include polymer(s) of beta-hydroxybutyrate, D,L-beta- hydroxybutyrate, butyrate, butyric acid, and/or triglyceride tributyrin.
  • the additional compound(s) may include berberine, dihydroberberine, and/or tetrahydroberberine.
  • pharmaceutically effective amounts of R-beta- hydroxybutyrate and amino acid may be administered for inducing and/or maintaining ketosis.
  • Implementations may include one or more of the following features.
  • the amount of R-beta-hydroxybutyrate to induce and/or maintain ketosis in an individual may be less than or equal to half of the amount of D,L-beta-hydroxybutyrate to induce and/or maintain the same level of ketosis (e.g., as measured by blood ketone levels).
  • the amount of R-beta-hydroxybutyrate to induce and/or maintain ketosis in an individual may be less than the amount of D,L-beta-hydroxybutyrate or L-beta-hydroxybutyrate to induce and/or maintain the same level of ketosis.
  • the composition may include approximately 1 g to approximately 5 grams of R-beta-hydroxybutyrate and approximately 0.5 to 2 g of amino acid.
  • the amino acid may include Leucine.
  • the composition may include a mixture and/or complex of the R-beta-hydroxybutyrate and amino acid. At least a portion of the R-beta-hydroxybutyrate may be complexed with the amino acid, in some implementations.
  • a portion of the R-beta-hydroxybutyrate may be administered in the composition as a salt and/or polymer and another portion of the R-beta- hydroxybutyrate may be administered as a complex with an amino acid (e.g., leucine).
  • the composition may include at least one R-beta-hydroxybutyrate salt (e.g., in additional to the pharmaceutically effective amounts of R-beta-hydroxybutyrate in the composition and/or as the pharmaceutically effective amounts of R-beta- hydroxybutyrate).
  • beta-hydroxybutyrate may administered simultaneously and/or sequentially with one or more other compounds (e.g., short chain, medium chain, and/or long chain fatty acids).
  • beta-hydroxybutyrate and/or one or more other compounds may be delivered mixed in a powdered, liquid, gel, and/or other appropriate form.
  • the beta-hydroxybutyrate and/or one or more other compounds may be administered via pills, tablets, capsules, other oral administration forms, intravenously, nasal sprays, sublingual tabs/strips, or topical delivery, rectal, other appropriate administration forms, and/or combinations thereof.
  • the described compositions may be administered via any appropriate administration method.
  • the described compositions may be administered enterally and/or parenterally.
  • the described composition may be administered via a tablet and/or capsule.
  • the described composition may be administered via tablet, capsule, powdered supplement; ready-to-drink formulation; topical product including transdermals; cosmeceutical product; foods such bars, cookies, gum, candy, functional foods; toothpaste, sublingual product; injection; intravenous fluids; beverages such as shots or energy shots; inhalers; sublinguals; and/or combinations thereof.
  • the described composition may be provided in a powdered form that allows the described composition to be sprinkled on food, mixed with a liquid to provide a beverage, directly administered.
  • the described compositions may be administered on an administration protocol to improve glucose tolerance (e.g., fasting glucose levels may be reduced and/or glucose metabolism may be improved), in some implementations.
  • the described compositions may be administered on an administration protocol to increase ketone levels (e.g., blood and/or urine ketone concentrations).
  • ketone levels e.g., blood and/or urine ketone concentrations.
  • the described compositions may be administered once a day, via a time released or extended release preparation, and/or multiple times a day.
  • the described composition may replace other pharmaceuticals taken for improving glucose tolerance, such as metformin, and/or be utilized in combination with one or more other pharmaceuticals, as appropriate.
  • an administration schedule may include administration of different berberine metabolite compositions at different periods.
  • berberine metabolite compositions may include at least a first composition and a second composition.
  • the first composition may include dihydroberberine.
  • the second composition may include dihydroberberine and a first additional compound that is capable of independently increasing blood ketone levels.
  • the first composition may be administered to an individual for a first period of time and the second composition may be administered to the same individual for a second period of time.
  • a third composition comprising dihydroberberine and a second additional compound that is different from the first additional compound may be administered.
  • the first and other compositions may be administered alternatively, sequentially, and/or in conjunction with each other (e.g., with a second and/or third composition).
  • the compound formulations e.g., dihydroberberine and/or which additional compounds are included
  • user preference e.g., taste, diseases, sensitivities
  • desired results e.g., fast induction of ketosis and/or maintenance
  • berberine metabolite such as dihydroberberine and/or tetrahydroberberine
  • other forms of dihydroberberine and/or tetrahydroberberine may be administered such as salts, complexes, and/or derivatives thereof.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dans divers modes de réalisation, des métabolites de berbérine, tels que la dihydroberbérine et/ou la tétrahydroberbérine, peuvent être administrés pour gérer les taux de glucose sanguin, augmenter les taux de cétones (par exemple, la concentration sanguine de cétones) et/ou à des fins thérapeutiques chez l'homme. L'administration d'une quantité pharmaceutiquement efficace de métabolites de berbérine, telle que la dihydroberbérine, peut réduire les taux de glycémie à jeun, améliorer la tolérance au glucose, et/ou améliorer la réponse à la cétone sanguine. Dans certains modes de réalisation, des métabolites de berbérine peuvent être administrés avec un ou plusieurs autres composés.
PCT/US2022/049036 2021-11-04 2022-11-04 Administration de métabolites de berbérine WO2023081409A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17/519,127 2021-11-04
US17/519,127 US20220202789A1 (en) 2016-04-19 2021-11-04 Administration of berberine metabolites

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WO2023081409A1 true WO2023081409A1 (fr) 2023-05-11

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170296520A1 (en) * 2016-04-19 2017-10-19 Keto Patent Group, Inc. Administration of berberine metabolites
US20170296501A1 (en) * 2016-04-19 2017-10-19 Keto Patent Group, Inc. Administration of butyrate, beta-hydroxybutyrate, and related compounds in humans
US20180021274A1 (en) * 2016-07-21 2018-01-25 Savind, Inc. Compositions comprising beta-hydroxybutyric acid and salt, and methods of using the same
US20190255028A1 (en) * 2016-04-19 2019-08-22 Keto Patent Group, Inc. Administration of berberine metabolites

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170296520A1 (en) * 2016-04-19 2017-10-19 Keto Patent Group, Inc. Administration of berberine metabolites
US20170296501A1 (en) * 2016-04-19 2017-10-19 Keto Patent Group, Inc. Administration of butyrate, beta-hydroxybutyrate, and related compounds in humans
US20190255028A1 (en) * 2016-04-19 2019-08-22 Keto Patent Group, Inc. Administration of berberine metabolites
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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