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    • 专利摘要:
    Ketogenic compositions, including a non-racemic mixture of beta-hydroxybutyrate (BHB) enriched with the R enantiomer are formulated to increase the body's level of the ketone in an individual. The non-racemic mixture of BHB is enriched with the R enantiomer to elevate the ketone bodies and increase the rate at which ketosis is achieved, even though it contains an amount of the S enantiomer sufficient to provide alternative benefits, as discussed in this document. In some aspects, a composition to increase the body's ketone level in an individual contains a dietary or pharmaceutically acceptable carrier and a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, in which the non-racemic mixture of R- beta-hydroxybutyrate and S-beta-hydroxybutyrate contain about 55% to 98% enantiomeric equivalents of R-beta-hydroxybutyrate and about 45% to about 2% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
    公开号:BR112020010332A2
    申请号:R112020010332-2
    申请日:2018-11-20
    公开日:2020-11-10
    发明作者:Gary Millet
    申请人:Axcess Global Sciences, Llc；
    IPC主号:
    专利说明:

    [001] [001] This document discloses mixed non-racemic beta-hydroxybutyrated compounds, salts, esters and compositions enriched with the beta-hydroxybutyrate R enantiomer and to produce high blood levels of ketone bodies in an individual.
    [002] [002] During periods of fasting, extreme exercise and / or low carbohydrate consumption, the reserves of glucose and glycogen in the body are used up quickly and can be depleted quickly. Failure to replenish glucose stores as they are depleted causes the body to shift metabolically to the creation and use of ketone bodies as energy ("ketosis"). Ketone bodies can be used by the body's cells as fuel to satisfy the body's energy needs, including the brain and heart. During prolonged fasting, for example, blood ketone levels can increase to 2-3 mmol / L or more. It is conventionally understood that when blood ketones rise above 0.5 mmol / L, the heart, brain and peripheral tissues are using ketone bodies (for example, beta-hydroxybutyrate and acetoacetate) as the main source of energy . This condition is known as ketosis. Between 1.0 mmol / L and 3.0 mmol / L, the condition is called "nutritional ketosis."
    [003] [003] After the transition to ketosis, or in other words, during ketogenic metabolism in the liver, the body uses dietary and body fats as the primary source of energy. Consequently, once in ketosis, one can induce the loss of body fat, controlling the dietary fat intake and maintaining low carbohydrate intake and blood level to support ketosis.
    [004] [004] While in ketosis, the body is in ketogenesis and essentially burns fat as a primary fuel. The body breaks down fats into fatty acids and glycerol and transforms fatty acids into acetyl-CoA molecules, which are subsequently transformed through ketogenesis into water-soluble ketone bodies beta-hydroxybutyrate (“β-hydroxybutyrate” or “BHB”), acetoacetate (also known as acetylacetonate) and acetone in the liver. Beta-hydroxybutyrate and acetoacetate are the ketone bodies used by the body to obtain energy, while acetone is removed and expelled as a by-product of ketogenesis.
    [005] [005] The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, improved brain metabolism, neuroprotection, muscle-sparing properties and better cognitive and physical performance. Science-based improvements in cell metabolism efficiency, managed through ketone supplementation, can have beneficial impacts on physical, cognitive and psychological health and a long-term impact on health with regard to common preventable diseases such as obesity, illness cardiovascular, neurodegenerative diseases, diabetes and cancer.
    [006] [006] Despite the many health benefits of following a ketogenic diet or lifestyle and maintaining a state of nutritional ketosis, there are still significant barriers in seeking and maintaining a ketogenic state. One of these barriers is the difficulty of transition to a ketogenic state. The fastest endogenous way to enter ketosis by depleting glucose stores in the body is fasting combined with exercise. This is physically and emotionally difficult and is extremely challenging, even for the most motivated and disciplined
    [007] [007] In addition, the transition to ketosis is usually accompanied by hypoglycemia, which can cause lethargy and dizziness in many, resulting in an uncomfortable physiological and mental state, commonly called "low-carb flu".
    [008] [008] If an individual is successful in establishing ketosis, the act of sustaining ketosis is equally difficult, if not more difficult, due to the need to maintain a rigid proportion in the diet of carbohydrates and proteins and fats. It is further complicated by the disruption of normal electrolyte balance that usually occurs when making the transition and maintaining a ketogenic state. The depletion and reduction of glycogen stores in the liver and muscles decreases the body's ability to retain water, leading to more frequent urination and, consequently, greater loss of electrolytes. In addition, the drop in insulin levels caused by ketosis affects the rate at which certain electrolytes are extracted by the kidneys, further decreasing the levels of electrolytes in the body. The negative effects of electrolyte imbalance include muscle pain, spasms, contractions and weaknesses, restlessness, anxiety, frequent headaches, severe thirst, insomnia, fever, heart palpitations or irregular heartbeat, digestive problems such as cramps, constipation or diarrhea, confusion and concentration problems, bone disorders, joint pain, changes in blood pressure, changes in appetite or body weight, fatigue (including chronic fatigue syndrome), numbness in the joints and dizziness, especially when you get up suddenly.
    [009] [009] Some compositions used to promote ketosis in a mammal include a racemic mixture of beta-hydroxybutyrate (RS-beta-hydroxybutyrate or DL-beta-hydroxybutyrate). Other compositions, such as those disclosed in US Patent Publication No. 2017/0296501 to Lowery and others, contain only the endogenous form of beta-hydroxybutyrate or R-beta-hydroxybutyrate, and none of the non-endogenous enantiomers or S-beta-hydroxybutyrate. Others, such as those disclosed in US Patent Number 2017/0296501 to Clarke et al., consist mainly or entirely of a single beta-hydroxybutyrate (3R) -hydroxybutyl (3R) -hydroxybutyrate ester. Other enantiomers, such as (3R) -hydroxybutyl (3S) - hydroxybutyrate, (3S) -hydroxybutyl (3R) - hydroxybutyrate and (3S) -hydroxybutyl (3S) - hydroxybutyrate, are mostly or entirely omitted. The omission of enantiomers that are not the endogenous form of beta-hydroxybutyrate is based on the view that S-beta-hydroxybutyrate (also known as (3S) - hydroxybutyrate) is ineffective or even harmful. BRIEF SUMMARY
    [010] [010] This document discloses ketogenic compositions and methods for increasing the level of the ketone body in an individual, including the promotion and / or maintenance of ketosis in an individual. Example compositions include a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, where the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains from 55% to 98% in enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 45% to 2% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
    [011] [011] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrate enantiomer, the endogenous form produced by a mammal, than the S-beta-hydroxybutyrate enantiomer in order to provide a greater and / or faster ketogenic effect compared to a racemic mixture. As the R-beta-hydroxybutyrate enantiomer is produced endogenously by a mammal during ketosis, administration of the R-beta-hydroxybutyrate enantiomer to an individual provides an additional amount and / or an increase in the blood plasma level that can be used immediately by the body, as to produce energy (for example, as an alternative energy source to glucose).
    [012] [012] Unlike compositions that deliberately minimize or eliminate S-beta-hydroxybutyrate, the non-racemic mixture contains a significant amount of the S-beta-hydroxybutyrate enantiomer, which is not endogenously produced by a mammal in order to produce a or more effects on the mammal, as discussed in this document
    [013] [013] In some embodiments, the compositions disclosed in this document can be used in a method to increase the level of ketone in an individual's body, including promoting and / or maintaining ketosis in an individual, comprising administration to an individual in need of a nutritionally or pharmaceutically effective amount of one or more of the compositions disclosed herein. Examples of beneficial effects of increasing the body's ketone level in an individual include one or more appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental alertness, increased physical energy, improved cognitive function, reduction of traumatic brain injury, reduction in the effect of diabetes, improvement of neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, anti-glycation, reduction of epileptic seizures, improvement of mood, increase in strength, increase in muscle mass or improvement in body composition.
    [014] [014] In some embodiments, administration of the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomeric proportions or percentages disclosed in this document provides one or more of: increased endogenous production of R-beta-hydroxybutyrate and acetoacetate ; endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of S-beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis; metabolism of S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and / or acetoacetate; increased fetal development; more years of growth; reduced endogenous acetone production during ketosis; signaling by S-beta-hydroxybutyrate that modulates the metabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-CoA.
    [015] [015] In some embodiments, the non-racemic mixture is a solid, such as a powder, crystalline or compressed material. In some embodiments, the composition may include a carrier, such as a liquid, gel or solid.
    [016] [016] Additional features and benefits will be set out in part in the description below and in part will be obvious from the description, or can be learned by practicing the modalities revealed in this document. It should be understood that both the brief summary above and the detailed description below are only exemplary and explanatory and are not restrictive of the modalities disclosed in this document or as claimed. DETAILED DESCRIPTION I. DEFINITIONS
    [017] [017] As used in this document, "beta-hydroxybutyrate", also known as β-hydroxybutyrate, βHB or BHB, means a compound with the general formula CH3CH2OHCH2COOH and the following chemical structure: where, X can be hydrogen, metal ions , amino acids, as of an amino acid, alkanyl, alkenyl or aryl.
    [018] [018] Whether the beta-hydroxybutyrate is the R- or S enantiomer depends on the tetrahedral orientation of the hydroxy (or oxy group in the case of an ester) on the 3-carbon (beta-carbon) in relation to the flat carboxyl group.
    [019] [019] Beta-hydroxybutyrate, normally R-beta-hydroxybutyrate, which is the endogenous form, can be used by the patient's body as an energy source during times of low glucose levels in the individual or when the patient's body is supplemented with a usable form of beta-hydroxybutyrate. Beta-hydroxybutyrate is commonly referred to as a “ketone body”
    [020] [020] As used herein, a "ketogenic composition" is formulated to increase the level of the ketone body in an individual, including inducing and / or maintaining a state of elevated ketone bodies at a desired level, such as ketosis, in an individual to whom it is administered.
    [021] [021] As used herein, "individual" or "patient" refers to members of the animal kingdom, including mammals, such as, without limitation, humans and other primates; rodents, fish, reptiles and birds. The individual can be any animal that requires therapy, treatment or prophylaxis, or any animal suspected of requiring therapy, treatment or prophylaxis. Prophylaxis means that the regimen is performed to prevent a possible occurrence, such as where a high glucose or diabetes is identified. "Patient" and "individual" are used interchangeably in this document.
    [022] [022] The term "ketosis", as used herein, refers to an individual with blood ketone levels in the range of about 0.5 mmol / L and about 16 mmol / L. Ketosis can improve mitochondrial function, decrease the production of reactive oxygen species, reduce inflammation and increase the activity of neurotrophic factors. "Keto-adaptation", as used in this document, refers to prolonged nutritional ketosis (> 1 week) to achieve sustained non-pathological "mild ketosis" or "therapeutic ketosis."
    [023] [023] In some cases, "elevated body level of ketone" may not mean that an individual is in a state of "clinical ketosis", but nevertheless has a high supply of ketones to produce energy and / or to perform other beneficial effects of ketone bodies. For example, an individual who is "adapted to the ketone" may not necessarily have elevated serum levels of ketone bodies in the blood, but is able to use the available ketone bodies more quickly compared to an individual who is not "adapted to the ketone." In this case, "elevated body level of ketone" may refer to the total amount and / or rate of ketone bodies being used by the individual, rather than the plasma levels of the blood itself.
    [024] [024] The term "medium chain triglycerides" (MCT) refers to molecules with a glycerol backbone attached to three medium chain fatty acids. Medium chain fatty acids can range from 6 to 12 carbon atoms in length and, more likely, from 8 to 10 carbon atoms. Examples of fatty acids are caprylic acid, also known as octanoic acid, comprising 8 carbon molecules, and capric acid, also known as decanoic acid, comprising 10 carbon molecules. MCTs, medium and mono chain fatty acids and di-glycerides are precursors of the ketone body that can provide an additional source for the production of ketone bodies independent of beta-hydroxybutyrate.
    [025] [025] The term "administer" or "administration" is used throughout this document to describe the process in which the disclosed compositions are released to an individual. The composition can be administered in a variety of ways, including oral, intragastric and parenteral (referring to intravenous and intra-arterial routes and other appropriate parenteral routes), among others. II. NON-RACEMIC COMPOSITIONS OF BETA-HYDROXYBUTIRATE
    [026] [026] Compositions for increasing the body's ketone level in an individual, including the promotion and / or maintenance of ketosis, comprise a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, in which the non-racemic mixture contains from 55% to 98% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 45% to 2% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.
    [027] [027] In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains from 55% to 95%, 55% to 89%, 57% to 87% or 60% to 80%, for example enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 45% to 5%, 45% to 11%, 43% to 13%, 41% to 15% or 40% to 20%, in enantiomeric equivalents of the S-beta-enantiomer of hydroxybutyrate.
    [028] [028] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains more of the R-beta-hydroxybutyrate enantiomer, the endogenous form produced by a mammal, than the S-beta-hydroxybutyrate enantiomer in order to provide a greater and / or faster ketogenic effect compared to a racemic mixture. Since the R-beta-hydroxybutyrate enantiomer is produced endogenously by a mammal during ketosis, administration of the R-beta-hydroxybutyrate enantiomer to an individual provides an additional amount and / or increased plasma blood level that can be used immediately by the body, as to produce energy (for example, as an alternative source of energy to glucose). The presence of the S enantiomer can modulate and prolong this effect.
    [029] [029] Unlike compositions that deliberately minimize or eliminate S-beta-hydroxybutyrate, the non-racemic mixture contains a significant amount of the S-beta-hydroxybutyrate enantiomer, which is not endogenously produced by a mammal in order to produce a or more desired effects on the mammal. For example, the administration of S-beta-hydroxybutyrate together with R-beta-hydroxybutyrate can result in at least one of the following factors: (1) increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; (2) endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of S-beta-hydroxybutyrate into fatty acids and sterols; (4) prolonged ketosis; (5) metabolism of S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and / or acetoacetate; (6) increased fetal development; (7) increased years of growth; (8) reduced endogenous acetone production during ketosis; (9) signaling by S-beta-hydroxybutyrate that modulates the metabolism of R-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11) production of acetyl-CoA.
    [030] [030] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be used, for example, to produce one or more desired effects on the individual, including, but not limited to, appetite suppression, weight loss, weight loss fat, reduced blood glucose level, improved mental alertness, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced diabetes effect, improved neurological disorder, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased strength, increased muscle mass or improved body composition.
    [031] [031] In some embodiments, the composition may include a vehicle.
    [032] [032] R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be supplied in various forms, such as salts and esters. The percentage of enantiomer equivalents for each of the R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is defined by the molar amount of R-beta-hydroxybutyrate or S-beta-hydroxybutyrate divided by the total molar amount of both R-beta - hydroxybutyrate and S-beta-hydroxybutyrate. The quantities of any cations that form salts and / or alcohols that form esters are excluded and do not count in determining the percentage of enantiomeric equivalents of each of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate.
    [033] [033] In order not to overload the composition with R-beta-hydroxybutyrate and a high amount of precursor that is readily converted to R-beta-hydroxybutyrate, that is, the monoester of R-1 3-butanediol and R-beta-hydroxybutyrate ( that is, (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester), the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate should not contain more than 88%, 87%, or 86%, or 85 % in enantiomeric equivalents of the (3R) - hydroxybutyl (3R) -hydroxybutyrate monoester.
    [034] [034] In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is provided in a composition that includes a dietary or pharmaceutically acceptable carrier. Examples include powders, liquids, tablets, capsules, food products, food additives, beverages, beverage additives, sweets, suction cups, lozenges, food supplements, sprays, injectables and suppositories.
    [035] [035] In some embodiments, the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be supplied as a salt, as one or more salts of alkali metals, alkaline earth metals, transition metals, amino acids or amino acid metabolites. Examples include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, zinc salts, iron salts (such as iron II and / or iron III), chromium salts, manganese salts, salts of cobalt, copper salts, molybdenum salts, selenium salts arginine salts, lysine salts, leucine salts, isoleucine salts, histidine salts, ornithine salts, citrulline salts, glutamine salts and creatine salts.
    [036] [036] In some embodiments, the non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate can be supplied as one or more esters, such as mono, di-, tri, oligo- and polyesters. Examples include ethanol monoester,
    [037] [037] In some embodiments, the composition may also include at least one medium chain fatty acid, or a mono, di or triglyceride of at least one medium chain fatty acid, where the medium chain fatty acid has 6 to 12 carbons, preferably 8 to 10 carbons. Although less preferred, the composition may comprise at least one short chain fatty acid, or a mono, di or triglyceride of at least one short chain fatty acid, having less than 6 carbons and / or at least one long chain fatty acid or a mono-, di- or triglyceride of at least one long-chain fatty acid, with more than 12 carbons.
    [038] [038] Examples and sources of medium chain fatty acid, or an ester thereof, such as a medium chain triglyceride, include coconut oil, powdered coconut milk, fractionated coconut oil, palm oil, palm kernel oil, , caprylic acid, capric acid, isolated fatty acid acids, such as isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid, purified or naturally occurring medium chain triglycerides, such as coconut oil, and ester derivatives of ethoxylated fatty acid triglycerides medium chain, enone triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives and triglyceride derivatives and medium chain triglyceride salts. Ester derivatives optionally include alkyl ester derivatives, such as methyl, ethyl, propyl, butyl, hexyl, etc.
    [039] [039] The administration of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate results in elevated and sustained blood levels of ketone bodies, thus exploring the metabolic and physiological advantages of sustained ketosis. Increased levels of ketone bodies in the blood provide the individual with greater flexibility in dietary options compared to methods that aim to induce and sustain ketosis based on diet alone (for example, based on fasting and / or limited intake of carbohydrates). For example, an individual who has been given an appropriate amount of a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate may occasionally eat carbohydrate or sugar based foods, without compromising the ketogenic state and changing back to glucose-based metabolic state. In addition, this administration facilitates the easier transition to a ketogenic state, while reducing or eliminating the harmful effects typically associated with entering ketosis.
    [040] [040] In some embodiments, a ketogenic composition additionally includes a therapeutically effective amount of vitamin D3. Vitamin D3 is believed to work in conjunction with magnesium and calcium to promote good bone health and to prevent undesirable soft tissue calcification.
    [041] [041] Some modalities also include one or more precursors or additional ketone supplements. These additional ketone precursors or supplements may include acetoacetate, ketone esters and / or other compounds that cause an increase in blood ketone levels without adding more electrolytes to the bloodstream. Other additives include metabolites that improve the effect or transport of ketone bodies to mitochondria, caffeine, theobromine and nootropics, such as L-alpha glycerylphosphorylcholine ("alpha GPC").
    [042] [042] The composition may include flavoring agents that help to mask the bad taste of beta-hydroxybutyrate compounds. These include essential oils such as peppermint, natural and artificial sweeteners and other flavorings known in the art.
    [043] [043] In some embodiments, ketogenic compositions may also include one or more additional components configured to decrease the composition's hygroscopicity. For example, various anti-caking agents, flow agents and / or moisture absorbers, in types and quantities safe for consumption, may be included. Such additional components may include one or more of an aluminosilicate salt, ferrocyanide, carbonate or bicarbonate, silicate (for example, sodium or calcium silicate), phosphate salt (for example, tricalcium phosphate), talc, powdered cellulose and the like . III. ADMINISTRATION
    [044] [044] In some embodiments, the compositions disclosed in this document can be used in a method to increase the level of the ketone body, including the promotion and / or maintenance of ketosis, in an individual who understands administration to an individual in need of nutritionally or pharmaceutically effective amount of one or more compositions disclosed herein. Examples of beneficial effects of increasing the body's ketone level, including promoting and / or maintaining ketosis, in an individual include one or more appetite suppression, weight loss, fat loss, reduced blood glucose level, alert improved mental, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced diabetes effect, improved neurological disorder, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizure, improved mood , increased strength, increased muscle mass, or improved body composition.
    [045] [045] In some embodiments, administration of the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in the enantiomeric proportions or percentages disclosed in this document provides one or more among increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of S-beta-hydroxybutyrate into fatty acids and sterols; prolonged ketosis; metabolism of S-beta-hydroxybutyrate independent of conversion to R-beta-hydroxybutyrate and / or acetoacetate; increased fetal development; more years of growth; reduced endogenous acetone production during ketosis; signaling by S-beta-hydroxybutyrate that modulates the metabolism of R-beta-hydroxybutyrate and glucose; antioxidant activity; and production of acetyl-CoA.
    [046] [046] The ketogenic compositions described in this document can be administered to an individual in therapeutically effective dosages and / or at frequencies to induce or sustain ketosis. In some embodiments, a single dose will include a non-racemic mixture of R-beta-hydroxybutyrate and
    [047] [047] In some embodiments, ketogenic compositions may include or be administered in conjunction with other supplements, such as vitamin D3, vitamins, minerals and others known in the art.
    [048] [048] In some embodiments, the compositions may also include one or more medium-chain fatty acids, fatty acid esters, or mono, di- or triglycerides of medium-chain fatty acids in order to provide an additional source of ketone bodies , as discussed in this document, to sustain ketosis for a long period of time, if compared only to the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate. In some embodiments, the composition is preferably administered so that the ratio of the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to medium-chain fatty acid (or ester thereof) ranges from about 4: 1 to about 1: 4 or about 2: 1 to about 1: 2 or about 1.5: 1 to about 1: 1.5.
    [049] [049] In some modalities, the individual preferably follows a ketogenic diet that restricts the intake of carbohydrates and proteins during the period of administration of the composition. In an exemplary modality, the individual can restrict food intake to a proportion of about 65% fat, about 25% protein and about 10% carbohydrates. The resulting therapeutic ketosis provides rapid and sustained keto-adaptation as a metabolic therapy for a wide range of metabolic disorders and provides nutritional support for therapeutic fasting, weight loss and performance enhancement.
    [050] [050] In a preferred embodiment, ketogenic compositions can be administered via oral administration in solid and / or powdered form, as in a powdered mixture (for example, powdered gelatin capsules), compressed tablets or another route of administration known to those skilled in the art.
    [051] [051] In some embodiments, multiple doses of the composition are administered over a period of time. The frequency of administration of the composition can vary depending on several factors, such as time elapsed from previous treatments, treatment goals and the like. The duration of administration of the composition (for example, the length of time the agent is administered) can vary depending on a variety of factors, including the individual's response, desired treatment effect, etc.
    [052] [052] The amount of the composition to be administered can vary according to factors such as the individual's degree of susceptibility, the individual's age, sex and weight, the individual's idiosyncratic responses and the like. The "therapeutically effective amount" is the amount necessary to promote a therapeutically effective result in vivo (i.e., therapeutic ketosis). According to the present disclosure, an adequate single dose amount is a dose capable of preventing or alleviating (reducing or eliminating) a symptom in a patient when administered one or more times over an appropriate period of time.
    [053] [053] The amount of the composition administered will depend on the rates of potency, absorption, distribution, metabolism and excretion of unused ketone bodies, electrolytes, method of administration and specific disorder to be treated, as well as other factors known to those skilled in the art. The dose should be sufficient to affect a desirable response, such as a therapeutic or prophylactic response against a specific disorder or condition, taking into account the severity of the condition to be relieved. The compounds can be administered once or they can be divided and administered over time intervals. It should be understood that the administration can be adjusted according to the individual need and professional judgment of a person who administers or supervises the administration of the compositions. IV. EXAMPLES
    [054] [054] The following is a description of exemplary non-racemic mixtures of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate compositions and other ketogenic compositions useful for raising ketone levels in an individual, including induction and / or maintenance of a ketogenic state in an individual to whom they are administered. It should be appreciated that the beta-hydroxybutyrate compounds described in the examples can be in the form of salts, esters, dimers, trimers, oligomers and polymers, as discussed herein.
    [055] [055] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 55% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 45% enantiomeric equivalents of the S- enantiomer
    [056] [056] The non-racemic mixture is readily administered as a ketogenic composition, as in powder form as a dietary supplement mixed with food or drink, in the form of one or more capsules or pills, or in liquid form as a mouth spray .
    [057] [057] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 57% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 43% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. As the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dose compared to the same dosage as the racemic or non-racemic mixture of Example 1. On the other hand, the inclusion of S-beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits, as disclosed herein, compared to a composition containing 90-100% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.
    [058] [058] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-
    [059] [059] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 65% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 35% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. As the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dose compared to the same dosage as the racemic mixture or the non-racemic mixtures of Examples 1-3. On the other hand, the inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits, as disclosed herein, compared to a composition containing 90-100% enantiomeric equivalents of the R-beta enantiomer - hydroxybutyrate.
    [060] [060] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more compounds of R-beta-
    [061] [061] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 75% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 25% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Since the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage compared to the same dosage as the racemic or non-racemic mixtures of Examples 1-5. On the other hand, the inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits, as disclosed herein, compared to a composition containing 90-100% enantiomeric equivalents of the R-beta enantiomer - hydroxybutyrate.
    [062] [062] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 80% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 20% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Since the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage compared to the same dosage as the racemic or non-racemic mixtures of Examples 1-6. On the other hand, the inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits, as disclosed herein, compared to a composition containing 90-100% enantiomeric equivalents of the R-beta enantiomer - hydroxybutyrate EXAMPLE 8
    [063] [063] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 85% enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 15% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Since the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dose compared to the same dosage as the racemic mixture or the non-racemic mixtures of Examples 1-7. On the other hand, the inclusion of the S-beta-hydroxybutyrate enantiomer provides a longer state of ketosis and / or other benefits, as disclosed herein, compared to a composition containing 90-100% enantiomeric equivalents of the R-beta enantiomer - hydroxybutyrate.
    [064] [064] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 89 % enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 11% enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. As the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage compared to the same dosage as the racemic or non-racemic mixtures of Examples 1-8.
    [065] [065] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% in enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 10%, 9%, 8%, 7%, 6 %, 5%, 4%, 3% or 2% in enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer, with the proviso that the non-racemic mixture does not contain more than 88% or 87% or 86% or 85% in equivalents enantiomers of the (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester (i.e., the R-1,3-butanediol and R-beta-hydroxybutyrate monoester). As the non-racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dose compared to the same dosage as the racemic mixture or the non-racemic mixtures of Examples 1-9.
    [066] [066] Any of the preceding examples is modified by combining the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with a dietary or pharmaceutically acceptable carrier.
    [067] [067] Any of the preceding examples is modified by combining the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more medium-chain triglycerides and / or one or more medium-chain fatty acids and / or one or more mono - or diglyceride medium chain fatty acids.
    [068] [068] Any of the preceding examples is modified by combining the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more supplements, such as vitamin D3, vitamins, minerals and others known in the art.
    [069] [069] The present invention can be incorporated in other specific forms without departing from its spirit or essential characteristics. The described modalities should be considered in all aspects only as illustrative and not restrictive. The scope of the invention, therefore, is indicated by the appended claims and not by the previous description. All changes that fall within the meaning and equivalence range of the claims must be adopted within their scope.
    权利要求:
    Claims (22)
    [1]
    1. Composition to increase the level of the ketone body in an individual, CHARACTERIZED by the fact that it comprises: a dietary or pharmaceutically acceptable vehicle; and a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, in which the non-racemic mixture contains from 55% to 98% in enantiomeric equivalents of R-beta-hydroxybutyrate and 45% to 2% in enantiomeric equivalents of S-beta-hydroxybutyrate.
    [2]
    2. Composition according to claim 1, CHARACTERIZED by the fact that the non-racemic mixture contains from 55% to 95% in enantiomeric equivalents of R-beta-hydroxybutyrate and 45% to 5% in enantiomeric equivalents of S-beta-hydroxybutyrate .
    [3]
    3. Composition according to claim 1 or 2, characterized by the fact that the non-racemic mixture contains from 55% to 89% in enantiomeric equivalents of R-beta-hydroxybutyrate and 45% to 11% in enantiomeric equivalents of S-beta -hydroxybutyrate.
    [4]
    Composition according to any one of claims 1 to 3, CHARACTERIZED by the fact that the non-racemic mixture contains 57% to 87% in enantiomeric equivalents of R-beta-hydroxybutyrate and 43% to 13% in enantiomeric equivalents of S -beta-hydroxybutyrate.
    [5]
    5. Composition according to any one of claims 1 to 4, CHARACTERIZED by the fact that the non-racemic mixture contains from 59% to 85% in enantiomeric equivalents of R-beta-hydroxybutyrate and 41% to 15% in enantiomeric equivalents of S -beta-hydroxybutyrate.
    [6]
    6. Composition according to any one of claims 1 to 5, CHARACTERIZED by the fact that the non-racemic mixture contains 60% to 80%
    in enantiomeric equivalents of R-beta-hydroxybutyrate and 40% to 20% in enantiomeric equivalents of S-beta-hydroxybutyrate.
    [7]
    Composition according to any one of claims 1 to 6, CHARACTERIZED by the fact that the composition comprises one or more R-beta-hydroxybutyrate salts.
    [8]
    Composition according to claim 7, characterized in that one or more R-beta-hydroxybutyrate salts comprise at least one of a sodium salt, potassium salt, magnesium salt, calcium salt, metal salt transition or amino acid salt.
    [9]
    9. Composition according to claim 8, CHARACTERIZED by the fact that the amino acid salt includes at least one amino acid or amino acid metabolite selected from arginine, lysine, leucine, isoleucine, histidine, ornithine, citrulline, glutamine or creatine.
    [10]
    10. Composition according to any one of claims 1 to 9, CHARACTERIZED by the fact that the non-racemic mixture contains at least one R-beta-hydroxybutyrate ester, with the proviso that the non-racemic mixture contains no more than 88% or 87%, or 86% or 85% enantiomeric equivalents of the (3R) -hydroxybutyl (3R) -hydroxybutyrate monoester.
    [11]
    11. Composition according to claim 10, CHARACTERIZED by the fact that the ester R-beta-hydroxybutyrate is a diester of a diol and R-beta-hydroxybutyrate.
    [12]
    12. Composition according to claim 10, CHARACTERIZED by the fact that the R-beta-hydroxybutyrate ester comprises at least one of ethanol monoester, 1-propanol monoester, 1,3-propanediol monoester, 1.3 diester - propanediol, mono or diester of S-1,3-butanediol, mono or diester of R-1,3-butanediol, mono or diester of SR-1,3-butanediol or mono, di- or triester of glycerin.
    [13]
    13. Composition according to any one of claims 1 to 12, CHARACTERIZED by the fact that the non-racemic mixture is a solid, such as a powder or crystalline material.
    [14]
    Composition according to any one of claims 1 to 13, CHARACTERIZED by the fact that the vehicle comprises a powder, a liquid, a tablet, a capsule, a food product, a food additive, a drink, a beverage additive or a food supplement.
    [15]
    15. Composition according to any one of claims 1 to 14, CHARACTERIZED by the fact that it further comprises vitamin D3, as in an amount of about 5 µg to about 200 µg, or about 10 µg to about 100 µg, or about 15 µg to about 75 µg, or in an amount of about 200 IU to about 8000 IU, or about 400 IU to about 4000 IU or about 600 IU to about 3000 IU.
    [16]
    16. Composition according to any one of claims 1 to 15, CHARACTERIZED by the fact that it further comprises at least one medium chain fatty acid, or a mono, di or triglyceride of at least one medium chain fatty acid.
    [17]
    17. Composition according to claim 16, CHARACTERIZED by the fact that at least one medium chain fatty acid has 6 to 12 carbons or 8 to 10 carbons.
    [18]
    18. Composition according to any one of claims 1 to 17, CHARACTERIZED by the fact that it further comprises at least one of (i) a short chain fatty acid, or a mono, di or triglyceride of at least one acid short chain fatty having less than 6 carbons or (ii) a long chain fatty acid, or a mono, di or triglyceride of at least one long chain fatty acid, with more than 12 carbons.
    [19]
    19. Composition to increase the level of the ketone body in an individual, CHARACTERIZED by the fact that it comprises: a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, in which the non-racemic mixture contains about 55% a 98% in R-beta-hydroxybutyrate enantiomeric equivalents and 45% to 2% in S-beta-hydroxybutyrate enantiomeric equivalents, with the proviso that the non-racemic mixture contains less than 85% in R-1 monoester enantiomeric equivalents , 3-butanediol and R-beta-hydroxybutyrate.
    [20]
    20. Method for increasing the level of the ketone body in an individual, CHARACTERIZED by the fact that it comprises administering to an individual in need of a nutritionally or pharmaceutically effective amount of the composition according to any one of claims 1 to 19.
    [21]
    21. Method according to claim 20, CHARACTERIZED by the fact that the increase in the level of the ketone body in the individual results in one or more of appetite suppression, weight loss, fat loss, reduced blood glucose level, alert improved mental, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced diabetes effect, improved neurological disorder, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased strength, increased muscle mass, or improved body composition.
    [22]
    22. Method according to claim 20 or 21, CHARACTERIZED by the fact that the administration of S-beta-hydroxybutyrate results in at least one of: increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of S-beta-hydroxybutyrate to one or both of R-beta-hydroxybutyrate and acetoacetate;
    endogenous conversion of S-beta-hydroxybutyrate into fatty acids and sterols;
    prolonged ketosis;
    metabolism of S-beta-hydroxybutyrate independent of conversion to R-
    beta-hydroxybutyrate and / or acetoacetate;
    increased fetal development;
    more years of growth;
    reduced endogenous acetone production during ketosis;
    signaling by S-beta-hydroxybutyrate that modulates the metabolism of R-beta-
    hydroxybutyrate and glucose;
    antioxidant activity;
    acetyl-CoA production.
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    同族专利:
    公开号 | 公开日
    US10588876B2|2020-03-17|
    AU2018370857A1|2020-06-11|
    SG11202004585UA|2020-06-29|
    JP2021504476A|2021-02-15|
    WO2019104082A1|2019-05-31|
    CA3083223A1|2019-05-31|
    EP3713560A4|2021-10-06|
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    US10245242B1|2019-04-02|
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    法律状态:
    2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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