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WO2018187852A1 - Compositions de butyrate et bêta-hydroxybutyrate et leurs procédés d'utilisation - Google Patents

Compositions de butyrate et bêta-hydroxybutyrate et leurs procédés d'utilisation Download PDF

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Publication number
WO2018187852A1
WO2018187852A1 PCT/CA2017/050646 CA2017050646W WO2018187852A1 WO 2018187852 A1 WO2018187852 A1 WO 2018187852A1 CA 2017050646 W CA2017050646 W CA 2017050646W WO 2018187852 A1 WO2018187852 A1 WO 2018187852A1
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Prior art keywords
butyrate
hydroxybutyrate
beta
purified
composition
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PCT/CA2017/050646
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English (en)
Inventor
Franco CAVALERI
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Cavaleri Franco
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Priority to EP17905469.7A priority Critical patent/EP3609484A4/fr
Priority to CA3053663A priority patent/CA3053663C/fr
Publication of WO2018187852A1 publication Critical patent/WO2018187852A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A23L33/165—Complexes or chelates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • compositions and methods of use thereof that comprise a combination of short chain fatty acids (such as butyrate) and ketones (such as beta-hydroxybutyrate), which provide the various health benefits described herein.
  • short chain fatty acids such as butyrate
  • ketones such as beta-hydroxybutyrate
  • ketosis is also a state desired by athletes in pursuit of improved performance, as a function of ketones serving as substrates for mitochondrial ATP generation.
  • Research shows that ketones produce as much as 38% more ATP per unit carbon than glucose as substrates of the TCA cycle.
  • ATP generation from ketones as substrates in the mitochondria instead of glucose results in fewer free radical by-products.
  • ketones are shown to induce transcription and subsequent synthesis of endogenous antioxidants, thereby priming the generation of intracellular glutathione and other endogenous antioxidants to produce a proactive protection against oxidative stress.
  • ketosis Athletes in ketosis and under physical load are shown to operate at full power output with a lower VO2 max than those utilizing glucose (carbohydrate) as a primary source of ATP.
  • ketones When at elevated serum levels indicative of ketosis, ketones are also known to spare muscle (anticatabolic) when under stress, including stress caused by nutrient deprivation.
  • ketosis is a metabolic state that does not fit optimally for everyone who attempts to achieve it, there are pharmacological benefits of ketones, such as beta-hydroxyl-butyrate / beta-hydroxybutyrate (BHB) and acetoacetate when they exist in hyperketonemic states. Healthy ketosis is represented by a state where ketones measure in the range 0.4 - 5.0 mmol/L, while blood sugar remains stable and at around baseline of 4.2-5.0 mmol/L.
  • ketones serve as substrates for efficient ATP generation
  • the means by which such ketones also serve as ligands for various receptors, such as hydroxyl carboxylic acid receptors (HCA) are not well understood.
  • BHB is a known HCA 2 receptor agonist and, therefore, it is expected to have some neuroprotective activity, vis-a-vis its activity on monocytes and macrophages.
  • ketones are hydrophilic and can cross to serve efficiently as substrates for neuron ATP generation.
  • Ketones can supply in excess of 50% of the brain's energy requirements during periods of glucose scarcity. The scarcity of glucose amid the abundantly available ketone causes cells to increase mitochondrial numbers, induce endogenous antioxidant generation, and activate various other protective mechanisms.
  • the exogenous supply of ketones may offer a number of pharmacological benefits, including both mental and physical benefits.
  • a daily supply of exogenous ketones would alleviate the stress associated with diet adherence, and would allow for the pharmacological benefits of ketones to continue due to the maintenance of elevated serum ketone levels (despite the temporary or prolonged increment of serum glucose and stored glycogen that may ensue as a function of a meal or few days off a ketogenic cycle).
  • An exogenous supplement of ketones would also provide an immediate and efficient transition back to a ketogenic lifestyle, without the associated energy deficit that is typically associated with the cell-switch-back to serum ketones and fat as an energy (ATP) substrate.
  • ATP energy
  • Metabolic support during energy substrate scarcity would be another substantial benefit of an exogenous ketone supply, particularly in the context of calorie or carbohydrate deprivation for weight management or therapy of other types.
  • An exogenously supply of ketones would further serve as a bridging energy source during a low-carbohydrate diet and fluctuations in dietary habits, whether those shifts are long-term initiatives or short-term breaks.
  • An exogenous supply of ketones would serve to avert the state of malaise that is often attendant to a calorie / carbohydrate deprived state, and would improve appetite control and support cognitive alertness.
  • Short chain fatty acids also known as volatile fatty acids, are those typically produced by the microbial community of the intestine. These microbes are often referred to as probiotics or microbiota. Such microbes comprise a significant component of the immune system. These symbiotic microbes produce short chain fatty acids from dietary fiber, i.e., fatty acids that serve as signaling ligands for various receptors involved in inflammatory control, including the HCA 2 receptor (the above described beta-hydroxy butyrate (ketone) serves as an agonist for such receptor as well).
  • HCA 2 receptor the above described beta-hydroxy butyrate (ketone) serves as an agonist for such receptor as well.
  • the short chain fatty acids of the intestinal lumen include most abundantly, butyrate, propionate, and acetate.
  • butyrate fed mice remain lean (despite dietary calorie load); avoid metabolic problems; have increased energy expenditure in the form of body heat generation; and tend to have higher physical activity.
  • Butyrate (BA) has been shown to lower serum cholesterol in various studies and by as much as 25% in some studies, and reduce serum triglycerides by as much as 50% compared to controls.
  • Butyrate has further been shown to lower fasting insulin by nearly 50%, and increase insulin sensitivity by as much as 300%. Still further, butyrate administration has been shown to improve appetite and food portion control.
  • butyrate is a key fuel for epithelial cells of the intestinal tract and that it may improve gut lining integrity. Similar to BHB, butyrate is an inhibitor of HDAC to induce global changes in genetic transcription of genes encoding oxidative stress resistance. This down regulation of gene transcription results in improved protection from free radical damage associated with strained or extreme metabolic conditions (and environmental toxins). This genetic optimization provided by butyrate also includes neuroprotection, similar to that exhibited by BHB.
  • lumen butyrate has been shown to directly preserve gut friendly bacteria in the microbiota, while adversely affecting pathogenic bacteria like Escherichia coli, Salmonella spp. and Campylobacter spp. Passive absorption of water in the colon depends on short chain fatty acid availability. Butyrate has been shown to play a role in healthy peristalsis to help normalize movement in cases of constipation or diarrhea. Butyrate serves to support optimal hydration and optimal bowel elimination function. Butyrate has also been shown to exhibit trophic effects on intestinal cell proliferation, improving villi, and general lining health.
  • butyrate has been shown to be a potent promoter of intestinal regulatory T cells establishing yet another immune regulating mechanism that promotes better inflammatory control at the mucosal lining. Promotion of gastrointestinal health provides a daunting platform for improved general and systemic health.
  • ketosis As described above, it is known from the literature that butyrate induces FGF21 in serum, liver and adipocytes, which in turn stimulates fatty acid oxidation and hepatic ketone production. This serves as an inducing signal for ketosis, along with butyrate itself, thereby serving as a direct substrate for ketone production and energy generation. In short, butyrate serves as a significant synergistic force for ketosis induction; BHB ligand interactions and pharmacology; and general health, fitness and performance support.
  • ketones such as BHB
  • ATP immediate alternative energy
  • butyrate supplementation in the form of sodium, calcium or potassium butyrate (or its esters) will prompt the body to induce endogenous ketone synthesis; will serve as a ligand to stimulate receptors that the ketone will act on; will contribute to the improvement of insulin and general metabolic health; will support inflammatory and general immune system health; will improve gastrointestinal health and integrity - all in parallel with the benefits that concurrent supplementation of the sister ketone molecule will provide.
  • compositions and methods of the present invention will be very useful for providing an exogenous supply of ketones, to provide a person with the numerous pharmacologic benefits described herein.
  • compositions include combinations of short chain fatty acids (e.g., butyrate) and ketones (e.g., beta- hydroxybutyrate), and/or derivatives of the foregoing.
  • short chain fatty acids e.g., butyrate
  • ketones e.g., beta- hydroxybutyrate
  • the compositions of the present invention offer a multitude of benefits and can be used for numerous applications.
  • oral formulations of such compositions may be used for sustaining elevated lumen and serum short chain fatty acid (SCFA) and/or ketone concentrations intended for therapeutic applications, such as body mass alteration, support of insulin activity, and support of cognitive activity (despite probiotic (microbiome) status and diet).
  • SCFA serum short chain fatty acid
  • the compositions of the invention may be useful for treating or preventing obesity, insulin resistance, metabolic syndromes, cognitive deficits, IBS, IBD, epilepsy, atrophy, and catabolism.
  • methods for increasing nuclear factor erythroid 2 related factor 2 (Nrf2) levels in a group of cells generally comprise administering to the cells a butyrate / beta-hydroxybutyrate composition described herein - e.g., a composition that comprises (a) purified butyrate or esters or propionate salts thereof and (b) purified beta-hydroxybutyrate or esters or propionate salts thereof.
  • the invention provides that such compositions may further be used to increase Nrf2 levels, e.g., by increasing Nrf2 expression, in cells that are subjected to chemical-induced stress.
  • Figure 1 a bar graph that shows the impact of treating BV2 cells with BHB-BA complex on Nrf2 levels (when the cells were treated for 30 minutes at concentrations of BHB-BA ranging from 0.4 mM to 2.4 mM).
  • Figure 2 a bar graph that shows the impact of treating LPS-stressed BV2 cells with BHB-BA complex on Nrf2 levels (when the cells were treated with BHB-BA complex at concentrations ranging from 0.4 mM to 2.4 mM).
  • Figure 3 a bar graph that further shows the impact of treating LPS-stressed BV2 cells with BHB-BA complex on Nrf2 levels (when the cells were treated with BHB- BA complex at concentrations ranging from 0.4 mM to 2.4 mM).
  • Figure 4 a line graph that shows the results of certain MTT assays using BV2 cells to measure cell stress and survival in the context of various BHB-BA and BHB-only treatment concentrations.
  • Figure 5 a line graph that summarizes a subject's (RG) serum glucose levels following administration of a BHB-BA combination of the present invention.
  • Figure 6 a line graph that summarizes a subject's (RG) serum ketone levels following administration of a BHB-BA combination of the present invention.
  • Figure 7 a line graph that summarizes a subject's (CD) serum glucose levels following administration of a BHB-BA combination of the present invention.
  • Figure 8 a line graph that summarizes a subject's (CD) serum ketone levels following administration of a BHB-BA combination of the present invention.
  • Figure 9 a line graph that summarizes a subject's (SD) serum glucose levels following administration of a BHB-BA combination of the present invention.
  • Figure 10 a line graph that summarizes a subject's (SD) serum ketone levels following administration of a BHB-BA combination of the present invention.
  • Figure 11 a line graph that summarizes a subject's (FC) serum glucose levels following administration of a BHB-BA combination of the present invention.
  • Figure 12 a line graph that summarizes a subject's (FC) serum ketone levels following administration of a BHB-BA combination of the present invention.
  • compositions providing a person with an exogenous and therapeutically effective supply of ketones are disclosed.
  • the compositions of the present invention may consist essentially of (a) purified butyrate (or esters or propionate salts thereof) and (b) purified beta-hydroxybutyrate (or esters or propionate salts thereof).
  • the invention provides that the compositions may further include other pharmacologically active agents, such as acetyl-L-carnitine, R-alpha lipoic acid, green tea extract, vitamins, and various combinations of such agents.
  • the invention provides that acetyl-L-carnitine (a source of L-carnitine following administration) has been shown to support cognition and mood; improve Alzheimer's symptoms; and support cardiovascular health.
  • a composition of the invention that includes acetyl-L-carnitine will be designed to support mitochondrial fatty acid oxidation in the context of a low carbohydrate diet and ketosis.
  • R-alpha lipoic acid will serve as an antioxidant and will support insulin sensitivity (i.e., to provide antioxidant protection in fat and water mediums and improve serum glucose clearance to facilitate ketosis and ketone prevalence as an energy substrate).
  • high-epigallocatechin gallate (EGCG) and high-caffeine green tea extract will provide a natural source caffeine to support beta oxidation of fatty acids and ketosis induction; it will supply a significant amount of EGCG for optimal antioxidant support; and it will provide anti-amylase activity to inhibit or slow carbohydrate digestion to result in an impaired glycemic index of and serum contribution by dietary carbohydrate sources, which promotes a ketogenic environment.
  • EGCG high-epigallocatechin gallate
  • high-caffeine green tea extract will provide a natural source caffeine to support beta oxidation of fatty acids and ketosis induction; it will supply a significant amount of EGCG for optimal antioxidant support; and it will provide anti-amylase activity to inhibit or slow carbohydrate digestion to result in an impaired glycemic index of and serum contribution by dietary carbohydrate sources, which promotes a ketogenic environment.
  • the methods generally include providing a person with an exogenous supply of ketones (or precursors thereof), by orally administering one of the pharmacologic compositions described herein, which is effective to deliver 1000 - 5000 mg of a short chain fatty acid (e.g., butyrate) and 1000 - 10,000 mg of ketone (e.g., beta-hydroxybutyrate) or, more preferably, which is effective to deliver 2000 - 5000 mg of butyrate and 5000 - 10,000 mg of beta-hydroxybutyrate to a person on a daily basis.
  • a short chain fatty acid e.g., butyrate
  • ketone e.g., beta-hydroxybutyrate
  • such compositions may be preferably delivered to a person in the form of oral capsules or dry powders.
  • compositions of the present invention may be administered in any desired and effective manner, e.g., as pharmaceutical compositions or nutritional supplements for oral ingestion. More particularly, for example, pharmaceutically acceptable compositions or nutritional supplements of the invention may comprise one or more of the compositions described herein with one or more acceptable carriers. Regardless of the route of administration selected, the compositions may be formulated into acceptable dosage forms by conventional methods known to those of skill in the art.
  • acceptable carriers include, but are not limited to, sugars (e.g., lactose, sucrose, mannitol, and sorbitol), silicon dioxide, starches, cellulose preparations (such as microcrystalline cellulose), calcium phosphates (e.g., dicalcium phosphate, tricalcium phosphate and calcium hydrogen phosphate), sodium citrate, water, aqueous solutions, alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol), polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), organic esters (e.g., ethyl oleate and tryglycerides), biodegradable polymers (e.g., polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils (e.g., corn, germ, olive,
  • Each acceptable carrier used in a pharmaceutical composition or nutritional supplement of the invention must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • Carriers suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable carriers for a chosen dosage form and method of administration can be determined using ordinary skill in the art.
  • compositions and nutritional supplements of the invention may, optionally, contain additional ingredients and/or materials commonly used in pharmaceutical compositions and/or nutritional supplements.
  • ingredients and materials include (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxy methyl cellulose and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monosterate;
  • compositions and nutritional supplements suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup, or a paste.
  • These formulations may be prepared by methods known in the art, e.g., by means of conventional pan-coating, mixing, granulation or lyophilization processes.
  • Solid dosage forms for oral administration may be prepared by mixing the active ingredient(s) with one or more acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, and/or coloring agents.
  • Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using a suitable excipient.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine.
  • the tablets, and other solid dosage forms, such as capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.
  • the tablets, and other solid dosage forms may also be formulated so as to provide slow or controlled release of the active ingredient therein. They may be sterilized by, for example, filtration through a bacteria-retaining filter.
  • These compositions may also optionally contain opacifying agents that release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • the active ingredient can also be in a microencapsulated form.
  • Liquid dosage forms for oral administration include acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain suitable inert diluents commonly used in the art.
  • the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions may contain suspending agents.
  • the present invention encompasses methods of using the beta-hydroxybutyrate / butyrate (BHB-BA) compositions described herein to modulate "nuclear factor erythroid 2 related factor 2" (Nrf2) levels. More particularly, the present invention encompasses methods of using the BHB-BA compositions described herein to increase Nrf2 levels in targeted cells.
  • Nrf2 is a transcription factor that transcribes a series of endogenous antioxidant defense systems. The transcription factor nucleotranslocates and binds the antioxidant response element (ARE) to transcribe cytoprotective genes.
  • ARE antioxidant response element
  • Nrf2 has been shown to transcribe the endogenous antioxidant peptides hemeoxygenase-1 , catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH/GPx) in response to stress as a preservation mechanism.
  • Nrf2 induction or overexpression has been shown to heighten cellular defense mechanisms during metabolic stress and convey neuroprotection during toxin-induced mitochondrial stress to the point of reduced lesion development. This cellular protection is also observed in the context of chemotherapy where concurrent Nrf2 induction protects healthy cells. Still further, Nrf2 induction has been shown to protect cells from LPS-induced inflammatory activity and mortality; Nrf2 signaling pathways are showing promise as a counteraction to mitochondrial dysfunction in Parkinson's disease; Nrf2 induction has been shown to convey critical defense against elevated serum-glucose-induced oxidative injury to cardiac muscle cells; and Nrf2 induction has been shown to provide a protective endogenous system against ischemic injury.
  • Nrf2 activation can be used as a therapeutic application to improve metabolic disorder and relieve renal damage associated with diabetes.
  • Nrf2 Nrf2
  • its role in cellular protection as a master regulator of antioxidant defense makes it a viable target for upregulation against toxicity in most organs and tissues of the body.
  • Nrf2 induction and overexpression there is a continued and growing demand for compositions that are associated with Nrf2 induction and overexpression - which, as demonstrated in Example 6 below, the BHB-BA compositions described herein have been shown to satisfy.
  • Example 1 The following Example describes a composition of the present invention, which includes butyrate salts (and/or esters or propionate salts thereof), in combination with beta-hydroxybutyrate salts (and/or esters or propionate salts thereof).
  • the target subject will preferably receive, on a daily basis, 1000 - 5000 mg of a short chain fatty acid (e.g., butyrate) and 1000 - 10,000 mg of ketone (e.g., beta-hydroxybutyrate) - or, more preferably, 2000 - 5000 mg of butyrate and 5000 - 10,000 mg of beta-hydroxybutyrate.
  • the invention provides that additional optimizing ingredients may be included in the formulation.
  • acetyl carnitine may be included, to provide a fatty acid transport mechanism facilitator.
  • R-alpha lipoic acid may be included to improve insulin efficacy and to drive serum glucose levels down to be conducive to ketogenesis and ketone body prevalence as an ATP substrate.
  • an approximate 2: 1 (butyrate : beta-hydroxybutyrate) ratio may be employed.
  • the invention provides that a 1 : 1 ratio can also be used, or other ratios that are deemed suitable for the mode of delivery and the body mass of the target subject (person).
  • the following provides an example formulation of the compositions of the present invention, showing a capsule formulation (at 1 : 1 and 2: 1 ratios of butyrate and beta-hydroxybutyrate) and a powder formulation.
  • Vitamin B6 pyridoxine 5'-phosphate 5 Vitamin B7 Biotin 0.5
  • Example 2 The following Example describes another composition of the present invention, which includes butyrate salts (and/or esters or propionate salts thereof), in combination with beta-hydroxybutyrate salts (and/or esters or propionate salts thereof).
  • the composition was formulated as individual capsules, which comprised the components set forth in the table below.
  • Example 6 - In this Example, four different subjects (RG, CD, SD, and FC) were each administered a combination of butyrate salts and beta-hydroxybutyrate salts at a 1 : 1 ratio (9.3 grams of such combination was solubilized in 350 mL of water). Each subject's serum glucose and serum ketone levels were subsequently measured at the time points listed in the applicable table below (the following data are further summarized in Figures 5 - 12).
  • Example 7 The following Example demonstrates the effects of the beta- hydroxy butyrate (BHB) / butyrate (BA) compositions described herein on "nuclear factor erythroid 2 related factor 2" (Nrf2). Specifically, Figure 1 shows the impact of treating BV2 cells (human microglia, brain-resident macrophage cells) with BHB-BA complex on Nrf2 levels.
  • BHB beta- hydroxy butyrate
  • BA butyrate
  • the BV2 cells were treated for 30 minutes at concentrations of BHB-BA complex ranging from 0.4 mM to 2.4 mM.
  • Figure 1 shows that the BHB-BA treatments increased Nrf2 levels by more than 22% over control (i.e., over the endogenous Nrf2 levels in the treated cells).
  • Figure 1 shows the impact of BHB-BA complex on Nrf2 levels in resting cells
  • Figure 2 shows the protective effects of BHB-BA complex (at concentrations ranging from 0.4 mM to 2.4 mM) when the BV2 cells are pretreated with the BHB-BA complex, prior to application of lipopolysacharride (LPS) induced stress. More specifically, the BV2 cells were pretreated with BHB-BA complex, prior to being subjected to LPS-induced stress for 30 minutes.
  • LPS lipopolysacharride
  • Nrf2 was shown to increase by as much as 30% over the control at 1.6 mM of BHB-BA complex, thereby preparing the stressed cells to compensate with a greater counterforce than that seen in resting non-stressed (non-LPS stimulated) cells. Nrf2 status was shown to level off at higher BHB-BA levels, which indicates there is no need to escalate BHB-BA levels beyond such levels (when elevation of Nrf2 levels is desired). Similar to Figure 2, Figure 3 shows yet additional and confirmatory data collected after treatment of BV2 cells with BHB-BA complex at concentrations ranging from 0.4 mM to 2.4 mM (wherein the cells were also stimulated with LPS for 30 minutes after pretreatment with the BHB- BA complex).
  • Figure 4 shows the results of certain MTT assays (colorimetric assays for assessing cell metabolic activity) using BV2 cells to measure cell stress and survival in the context of various BHB-BA treatment concentrations (based on BHB concentrations established by the treatment). As shown in Figure 4, the percent survival scores demonstrate that BHB-BA treatment achieves a healthier response in relation to the less preferable / survival outcome in the BHB-only group.

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Abstract

La présente invention concerne des compositions et des procédés fournissant à une personne une dose exogène et thérapeutiquement efficace de cétones. Les compositions peuvent essentiellement être constituées (a) de butyrate purifié (ou des esters ou ses sels propionate) et (b) de bêta-hydroxybutyrate purifié (ou des esters ou ses sels propionate). Les compositions peuvent en outre comprendre d'autres agents pharmacologiquement actifs, tels que de l'acétyl-L carnitine, de l'acide R-alpha lipoïque, de l'extrait de thé vert, des vitamines, et diverses combinaisons de tels agents. Les procédés consistent à fournir quotidiennement à une personne une dose exogène de cétones, en administrant par voie orale une composition pharmacologique, qui est efficace pour délivrer de 2 000 à 5 000 mg d'un acide gras à courte chaîne (par exemple, du butyrate) et de 5 000 à 10 000 mg de cétone (par exemple, du bêta-hydroxybutyrate). De plus, l'invention concerne des procédés d'augmentation des niveaux du facteur apparenté au facteur nucléaire érythroïde (2) (Nrf2) dans un groupe de cellules, lesquels consistent à administrer les compositions décrites ci-dessus au groupe des cellules.
PCT/CA2017/050646 2017-04-12 2017-05-29 Compositions de butyrate et bêta-hydroxybutyrate et leurs procédés d'utilisation WO2018187852A1 (fr)

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WO2020186154A1 (fr) * 2019-03-14 2020-09-17 The Regents Of The University Of California Procédés et compositions pour la prise en charge de la santé rénale
CN113660930A (zh) * 2019-02-11 2021-11-16 阿克塞斯全球科学有限责任公司 β-羟基丁酸盐混合盐-酸组合物和使用方法
CN115835786A (zh) * 2020-02-06 2023-03-21 阿克塞斯全球科学有限责任公司 对映纯的R-β-羟基丁酸混合盐-酸组合物
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US11950616B2 (en) 2019-06-21 2024-04-09 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US12090129B2 (en) 2017-11-22 2024-09-17 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US12128020B2 (en) 2016-04-19 2024-10-29 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans
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US12167993B2 (en) 2019-06-21 2024-12-17 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US12186297B2 (en) 2020-08-26 2025-01-07 Axcess Global Sciences, Llc Compositions and methods for increasing lean-to-fat mass ratio
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US12433912B2 (en) 2024-08-26 2025-10-07 Axcess Global Sciences, Llc Autobiotic compositions and method for promoting healthy gut microbiome

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US12350243B2 (en) 2016-04-19 2025-07-08 Axcess Global Sciences, Llc Compositions and compounds containing beta-hydroxybutyrate and one or more amino acids
US12251362B2 (en) 2016-04-19 2025-03-18 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans
US12128020B2 (en) 2016-04-19 2024-10-29 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans
US12090129B2 (en) 2017-11-22 2024-09-17 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US12329734B2 (en) 2017-12-19 2025-06-17 Axcess Global Sciences, Llc Use of S-beta-hydroxybutyrate compounds for induction and maintenance of flow
US11944598B2 (en) 2017-12-19 2024-04-02 Axcess Global Sciences, Llc Compositions containing s-beta-hydroxybutyrate or non-racemic mixtures enriched with the s-enatiomer
CN113660930A (zh) * 2019-02-11 2021-11-16 阿克塞斯全球科学有限责任公司 β-羟基丁酸盐混合盐-酸组合物和使用方法
WO2020186154A1 (fr) * 2019-03-14 2020-09-17 The Regents Of The University Of California Procédés et compositions pour la prise en charge de la santé rénale
US11013705B2 (en) 2019-03-14 2021-05-25 The Regents Of The University Of California Methods and compositions for supporting renal health
US11950616B2 (en) 2019-06-21 2024-04-09 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US12167993B2 (en) 2019-06-21 2024-12-17 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
CN115835786A (zh) * 2020-02-06 2023-03-21 阿克塞斯全球科学有限责任公司 对映纯的R-β-羟基丁酸混合盐-酸组合物
US12186297B2 (en) 2020-08-26 2025-01-07 Axcess Global Sciences, Llc Compositions and methods for increasing lean-to-fat mass ratio
US12144814B2 (en) 2023-03-10 2024-11-19 Axcess Global Sciences, Llc Compositions containing paraxanthine and beta-hydroxybutyrate or precursor for increasing neurological and physiological performance
US12439945B2 (en) 2024-05-13 2025-10-14 VitaNav, Inc. Method of improving flavor of a composition of (D)-β-hydroxybutyric acid and (D)-1,3 butanediol and use as a nutritional supplement and therapeutic agent
US12433912B2 (en) 2024-08-26 2025-10-07 Axcess Global Sciences, Llc Autobiotic compositions and method for promoting healthy gut microbiome

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