AU2020221569B2 - Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use - Google Patents
Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of useInfo
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Abstract
Ketogenic compositions include a racemic mixture of R- and S-beta-hydroxybutyric acids and a racemic mixture of R- and S-beta-hydroxybutyrate salts. The compositions contain the R-enantiomer to elevate ketone bodies and increase the rate at which ketosis is achieved and yet contain an equivalent amount of the S-enantiomer to provide alternative benefits. The R- and S-beta-hydroxybutyric acids are more rapidly absorbed and utilized by the body than salts or esters, enhance taste, and reduce the need to include citric acid or other edible acids. The R- and S-beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and can provide one or more electrolytes. The ketogenic composition may contain a dietetically or pharmaceutically acceptable carrier and a racemic mixture of R- and S-beta-hydroxybutyrate salts and acids. The composition contains less than 100% by molar equivalents of total R,S-beta-hydroxybutyrate salts and more than 0% by molar equivalents of R,S-beta-hydroxybutyric acids.
Description
RACEMIC BETA-HYDROXYBUTYRATE MIXED SALT-ACID COMPOSITIONS AND METHODS OF USE BACKGROUND 1. Field of The Invention
[0001] Disclosed herein are racemic beta-hydroxybutyrate compounds, particularly salts
and acids of racemic beta-hydroxybutyrate, and use of racemic beta-hydroxybutyrate
mixed salt-acid compositions for producing elevated blood levels of ketone bodies in a
subject.
2. Related Technology
[0002] In periods of fasting, extreme exercise, and/or low carbohydrate consumption,
glucose and glycogen stores in the body are rapidly used and can become quickly
depleted. Failure to replenish glucose stores as they become depleted causes the body to
metabolically metabolicallyshift to to shift the the creation and use creation andofuse ketone bodies for of ketone energy bodies ("ketosis"). for energy ("ketosis").
Ketone bodies can be used by cells of the body as a 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 (e.g., beta-hydroxybutyrate and acetoacetate) as the primary fuel
source. This condition is referred to as ketosis. At blood levels between 1.0 mmol/L and
3.0 mmol/L the condition is called "nutritional ketosis."
[0003] Upon transitioning into ketosis, or in other words, during ketogenic metabolism
in the liver, the body uses dietary and bodily fats as a primary energy source.
Consequently, once in ketosis, one can induce loss of body fat by controlling dietary fat
intake and maintaining low carbohydrate intake and blood level to sustain ketosis.
[0004] During ketosis, the body is in ketogenesis and essentially burning fat for its
primary fuel. The body cleaves fats into fatty acids and glycerol and transforms fatty
acids into acetyl CoA molecules, which are then eventually transformed through
ketogenesis into the water-soluble ketone bodies beta-hydroxybutyrate (i.e., "B-
hydroxybutyrate" or "BHB"), acetoacetate (also known as acetylacetonate), and acetone
in the liver. Beta-hydroxybutyrate and acetoacetate are the primary ketone bodies used
by the body for energy while acetone is removed and expelled as a by-product of
ketogenesis.
[0005] The metabolism of ketone bodies is associated with several beneficial effects,
including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle
-Page -Page 1-
WO wo 2020/167690 PCT/US2020/017552 PCT/US2020/017552
sparing properties, and improved cognitive and physical performance. Science-based
improvements in efficiency of cellular metabolism, managed through ketone
supplementation, have beneficial impacts on physical, cognitive health, and
psychological health, and a long-term impact on health with respect to common
avoidable diseases such as obesity, cardiovascular disease, neurodegenerative diseases,
diabetes, and cancer.
[0006] Despite the many health advantages of pursuing a ketogenic diet or lifestyle and
maintaining a state of nutritional ketosis, there remain significant barriers to pursuing
and maintaining a ketogenic state. One of these barriers is the difficulty of transitioning
into a ketogenic state. The fastest endogenous way to enter ketosis is by depleting
glucose stores in the body through fasting combined with exercise. This is physically and
emotionally demanding and is extremely challenging even for the most motivated and
disciplined.
[0007] Additionally, the transition into ketosis is often accompanied by hypoglycemia,
which can cause lethargy and light-headedness in many, resulting in an uncomfortable
physiological and mental state commonly referred to as the "low-carb flu." In addition,
many people experience a down regulation in their metabolism as the body naturally
goes into an "energy-saving" mode. Some suggest that these transitory symptoms may
last as long as two to three weeks. During this transition period, if a subject consumes a
meal or snack containing carbohydrates above the restrictive amount, there is an
immediate termination of ketogenesis, exiting the body from its state of ketosis. The
body then shifts back to glucose utilization for its primary fuel and the transition into
ketosis must begin anew.
[0008] If a subject is successful in establishing ketosis, the act of sustaining ketosis is
likewise difficult, if not more difficult, due to the need to maintain a rigid dietary ratio of
carbohydrates and protein to fats. It is further complicated by the disruption of normal
electrolyte balances that often occurs when transitioning into and maintaining a
ketogenic state. The depletion and lowering of glycogen stores in the liver and muscles
lessens the ability of the body to retain water, leading to more frequent urination, and
accordingly, a greater loss of electrolytes. Further, the reduction in insulin levels caused
by ketosis effects the rate at which certain electrolytes are extracted by the kidneys,
which can additionally lower electrolyte levels in the body. Negative effects of
electrolyte imbalance include muscle aches, spasms, twitches and weakness, restlessness,
anxiety, frequent headaches, feeling very thirsty, insomnia, fever, heart palpitations or
- Page 2 - irregular heartbeats, digestive issues such as cramps, constipation or diarrhea, confusion and trouble concentrating, bone disorders, joint pain, blood pressure changes, changes in appetite or body weight, fatigue (including chronic fatigue syndrome), numbness in joints, and dizziness, especially when standing up suddenly.
[0009]
[0009] Some Somecompositions usedused compositions to promote ketosis to promote in a mammal ketosis in a include mammal those disclosed include those disclosed
in U.S. Patent Publication No. 2017/0296501 to Lowery et al., which contain the
endogenous form of beta-hydroxybutyrate, or R-beta-hydroxybutyrate, while Lowery et
al. discourage use of the non-endogenous enantiomer, or S-beta-hydroxybutyrate, and
racemic mixtures of R-and S-beta-hydroxybutyrate. Others, such as those disclosed in
U.S. Patent No. 8,642,654 to Clarke et al. consist mostly or entirely of a single beta-
hydroxybutyrate ester (3R)-hydroxybutyl (3R)-hydroxybutyrate. The omission of
enantiomers that are not the endogenous form of beta-hydroxybutyrate is based on the
view that S-beta-hydroxybutyrate (aka (3S)-hydroxybutyrate) is ineffective or even
harmful.
[0010] Disclosed herein are racemic R,S-beta-hydroxybutyrate mixed salt-acid
compositions and methods of use in increasing ketone body level in a subject, including
promoting and/or sustaining ketosis in a subject over an extended period of time.
[0011] The racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions disclosed
herein comprise a racemic mixture of R-beta-hydroxybutyrate salt(s) and S-beta-
hydroxybutyrate salt(s) ("R,S-beta-hydroxybutyrate salts") and a racemic mixture of R-
beta-hydroxybutyric acid and S-beta-hydroxybutyric acid ("R,S-beta-hydroxybutyric
acids"). A "racemic mixture" of R,S-beta-hydroxybutyrate salts includes enantiomerically equivalent amounts (50:50) of R- and S-beta-hydroxybutyrate salts. A
"racemic mixture" of R,S-hydroxybutyric acids includes enantiomerically equivalent
amounts (50:50) of R- and S-beta-hydroxybutyric acids.
[0012] R-beta-hy droxy butyrate R-beta-hydroxybutyrate isis the the endogenous endogenous form form produced produced byby a a mammal, mammal, and and S-S-
beta-hydroxybutyrate enters the body through exogenous supplementation through the
administration of a racemic RS-beta-hydroxybutyrate mixed salt-acid composition. The
racemic RS-beta-hydroxybutyrate mixed salt-acid composition thus includes separate
components which function differently in the body but together provide enhanced
ketogenic effects, including greater sustained blood ketone levels compared to the
administration of only R-beta-hydroxybutyrate compounds. The R,S-beta- hydroxybutyrate mixed salt-acid compositions provide at least a "double racemic stack"
- Page 3 - of beta-hydroxybutyrate compounds.
[0013] The R-beta-hydroxybutyrate enantiomer is endogenously produced by a mammal
during ketosis, and the exogenously administered R-beta-hydroxybutyrate mixed salt-
acid components thus provide an additional quantity and/or increased blood plasma level
of of R-beta-hy droxy butyrate that R-beta-hydroxybutyrate cancan that be immediately utilized be immediately by the by utilized body, thesuch as for body, such as for
producing energy (e.g., as an alternative energy source to glucose). The S-beta-
hydroxybutyrate components, which are not endogenously produced by a mammal,
complement the R-beta-hydroxybutyrate components, and produce one or more desired
effects in the mammal not produced by the R-beta-hydroxybutyrate components.
[0014] For example, administering the S-beta-hydroxybutyrate mixed salt-acid
components along with the R-beta-hy droxy butyrate R-beta-hydroxybutyrate mixed mixed salt-acid salt-acid components components inin
enantiomerically equivalent ratios can result in at least one of: (1) increased endogenous
production productionofofR-beta-hy droxy butyrate and and R-beta-hydroxybutyrate acetoacetate; (2) endogenous acetoacetate; conversion (2) endogenous of conversion of
the S-beta-hydroxybutyrate components into one or both of R-beta-hydroxybutyrate and
acetoacetate; (3) endogenous conversion of the S-beta-hydroxybutyrate components into
fatty acids and sterols; (4) prolonged ketosis; (5) metabolism of the S-beta-
hydroxybutyrate components independent of conversion to R-beta-hydroxybutyrate
and/or acetoacetate; (6) increased fetal development; (7) increased growth years; (8)
reduced endogenous production of acetone during ketosis; (9) signaling by the S-beta-
hydroxybutyrate components that modulates metabolism of R-beta-hydroxybutyrate and
glucose; (10) antioxidant activity; and (11) production of facetyl-CoA. acetyl-CoA.
[0015] Exogenous delivery of a racemic R,S-beta-hydroxybutyrate mixed salt-acid
composition can beneficially provide a relatively rapid boost to blood ketone body
levels, primarily by way of the R-beta-hydroxybutyrate mixed salt-acid components,
particularly R-beta hydroxybutyric acid, in addition to a relatively more sustained
addition to blood ketone body level primarily by way of the S-beta-hydroxybutyrate
mixed salt-acid components. Such racemic R,S-beta-hydroxybutyrate mixed salt-acid
compositions are thus capable of effectively and relatively rapidly aiding a subject in
inducing ketosis, while simultaneously providing for sustained and prolonged delivery of
ketone bodies to the blood stream by virtue of the modulating effects of the S-beta-
hydroxybutyrate mixed salt-acid components in providing ketogenic benefits as required
by the body.
[0016] Combining R,S-beta-hydroxybutyric acid with one or more R,S-beta- hydroxybutyrate salts is highly beneficial because it reduces electrolyte load, increases
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WO wo 2020/167690 PCT/US2020/017552 PCT/US2020/017552
absorption rate, improves taste, facilitates easier formulation, and reduces the need to add
citric acid or other edible acids to obtain a composition having neutral or acidic pH.
[0017] In some embodiments, the racemic R,S-beta-hydroxybutyrate R,S-beta-hy droxybutyratemixed mixedsalt-acid salt-acid
compositions described herein may be combined with (e.g., directly admixed with or co-
administered with) one or more other dietetically and/or pharmaceutically acceptable
supplements/drugs to form a combination supplement. The unique properties of a
racemic R,S-beta-hydroxybutyrate mixed salt-acid composition may beneficially
enhance the combination supplement as compared to an otherwise similar combination
supplement using a beta-hydroxybutyrate composition consisting of or enriched with
either R-beta-hydroxybutyrate or S-beta-hydroxybutyrate. For example, a composition
intended to increase lipolysis and/or fat oxidation (referred to herein as a "fat burner"
component) may be combined with a racemic R,S-beta-hydroxybutyrate mixed salt-acid
composition to form a combination supplement with synergistic lipolysis and/or fat
burning effects. In another example, a composition intended to increase enhance mental
alertness, cognition, and/or mood (referred to herein as a "nootropic" component) may
be combined with a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition to
form a combination supplement with synergistic cognitive, alertness, and/or mood
effects.
[0018] In some embodiments, the racemic R,S-beta-hydroxybutyrate mixed salt-acid
compositions disclosed herein can be used in a method for increasing ketone body level
in a subject, including promoting and/or sustaining ketosis in a subject, comprising
administering to a subject in need thereof a nutritionally or pharmaceutically effective
amount of one or more compositions disclosed herein. Examples of beneficial effects of
increased ketone body level in a subject include one or more of appetite suppression,
weight loss, fat loss, reduced blood glucose level, improved mental alertness,
anxiolytic effects (anti-anxiety), faster reaction time, increased physical energy,
improved cognitive function, reduction in traumatic brain injury, reduction in effect
of diabetes, improvement of neurological disorder, reduction of cancer, reduction of
inflammation, anti-aging, antiglycation, reduction in epileptic seizer, improved mood,
increased strength, increased muscle mass, or improved body composition.
[0019] The composition may include a nutritionally or pharmaceutically acceptable
carrier.
[0020] Embodiments include a "racemic stack" of at least four different beta-
hydroxybutyrate compounds. R-beta-hydroxybutyrate and S-beta-hydroxybutyrate are
- Page 5 - provided asas free free acids acids (i.e., (i.e., R-beta-hydroxybutyric acidand andS-beta-hydroxybutyric S-beta-hydroxybutyric acid), salts 16 Apr 2025 2020221569 16 Apr 2025 provided R-beta-hydroxybutyric acid acid), salts thereof (i.e., thereof (i.e.,R-beta-hydroxybutyrate salt(s) and R-beta-hydroxybutyrate salt(s) and S-beta-hydroxybutyrate salt(s)), and S-beta-hydroxybutyrate salt(s)), optionally and optionally esters thereof (i.e., esters thereof (i.e., R-beta-hydroxybutyrate ester(s)andand R-beta-hydroxybutyrate ester(s) S-beta-hydroxybutyrate S-beta-hydroxybutyrate ester (s)). ester (s)).
Providing beta-hydroxybutyrate Providing beta-hydroxybutyrateas as a double a double racemic racemic stack stack thatthat combines combines at least at least four four separate separate
5 forms 5 forms (or (or triple triple racemic racemic stack stack thatthat combines combines six separate six separate forms) forms) of beta-hydroxybutyrate of beta-hydroxybutyrate may may beneficially allow beneficially the use allow the use of of higher higher amounts amountsofofbeta-hydroxybutyrate beta-hydroxybutyrate for for a given a given administered administered
dose and/orallow allowforformore more doses per day. Eachofform of beta-hydroxybutyrate is typically 2020221569
dose and/or doses per day. Each form beta-hydroxybutyrate is typically
associated with associated with itsits own own particular particular positive positive attributes attributes and negative and negative side effects. side effects. Stacking Stacking different different
forms of beta-hydroxybutyrate forms of beta-hydroxybutyrateallows allowsfor fordelivery deliveryofofmore moreofofthe thepositive positiveattributes attributes compared compared toto
10 10 each beingused each being usedalone. alone.Similarly, Similarly,stacking stackingdifferent differentforms formsof of beta-hydroxybutyrate beta-hydroxybutyrate reduces reduces or or
mitigates mitigates the the negative side effects negative side effects of of each each particular particular form form of of beta-hydroxybutyrate beta-hydroxybutyrate sosothat thatsuch such negative effects negative effects can can be be “spread-out” andlimited. "spread-out" and limited. In In either either case, case,stacking stackingincreases increasesor ormaximizes maximizes
the overall dose of beta-hydroxybutyrate that can be efficaciously delivered. the overall dose of beta-hydroxybutyrate that can be efficaciously delivered.
[0020A]
[0020A] In some In someembodiments, embodiments, therethere is disclosed is disclosed a racemic a racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate
15 mixed 15 mixed salt-acid salt-acid composition composition for for increasing increasing ketone ketone level level in in a subject,comprising: a subject, comprising: aa racemic racemic mixture mixture ofofbeta-hydroxybutyric beta-hydroxybutyric acids acids containing containing 50% 50%by by enantiomeric enantiomeric
equivalents of R-beta-hydroxybutyric equivalents of R-beta-hydroxybutyric acid acid and and 50% 50% by by enantiomeric enantiomeric equivalents equivalents of S-beta- of S-beta-
hydroxybutyricacid; hydroxybutyric acid;and and aa racemic racemic mixture mixture ofofbeta-hydroxybutyrate beta-hydroxybutyrate salts salts containing containing 50% 50%bybyenantiomeric enantiomeric 20 equivalents ?O equivalents of of oneone or or more more R-beta-hydroxybutyrate R-beta-hydroxybutyrate saltssalts and and 50% 50% by enantiomeric by enantiomeric equivalents equivalents of of one or more one or moreS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts, salts, wherein wherein the the beta-hydroxybutyrate beta-hydroxybutyrate saltssalts are selected are selected
from: from:
sodium R-beta-hydroxybutyrate; sodium R-beta-hydroxybutyrate;
potassiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; 25 25 calcium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate;
magnesium magnesium R-beta-hydroxybutyrate; R-beta-hydroxybutyrate;
sodium S-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate;
potassiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calcium S-beta-hydroxybutyrate;and calcium S-beta-hydroxybutyrate; and 30 30 magnesium magnesium S-beta-hydroxybutyrate; S-beta-hydroxybutyrate;
whereinthe wherein thecomposition composition comprises comprises 75% 75% to 99.9% to 99.9% by equivalents by molar molar equivalents of the racemic of the racemic
mixture of mixture of beta-hydroxybutyrate beta-hydroxybutyratesalts salts and and25% 25%toto0.1% 0.1%by by molar molar equivalents equivalents of of thethe racemic racemic
-Page6- -Page 6- mixture of of beta-hydroxybutyric beta-hydroxybutyricacids, acids, wherein whereinthe thecomposition compositionisisininsolid solid and/or and/or powder powderform. form. 16 Apr 2025 2020221569 16 Apr 2025 mixture
[0020B] In some
[0020B] In someembodiments, embodiments, there there is is racemicR,S-beta-hydroxybutyrate discloseda aracemic disclosed R,S-beta-hydroxybutyrate mixed mixed salt- salt-
acid composition acid composition for for increasing increasing ketone ketone level level in in a subject, a subject, comprising: comprising:
aa racemic racemic mixture mixture ofofbeta-hydroxybutyric beta-hydroxybutyric acids acids containing containing 50% 50%by by enantiomeric enantiomeric
5 5 equivalents of R-beta-hydroxybutyric equivalents of R-beta-hydroxybutyric acid acid and and 50% 50% by by enantiomeric enantiomeric equivalents equivalents of S-beta- of S-beta-
hydroxybutyricacid; hydroxybutyric acid; and and aa racemic racemic mixture mixture ofofbeta-hydroxybutyrate beta-hydroxybutyrate salts salts containing containing 50% 50%bybyenantiomeric enantiomeric 2020221569
equivalents equivalents of of one one or or more R-beta-hydroxybutyrate more R-beta-hydroxybutyrate saltsand salts and50% 50%by by enantiomeric enantiomeric equivalents equivalents of of
one or more one or moreS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts, salts, wherein wherein the the beta-hydroxybutyrate beta-hydroxybutyrate saltssalts are selected are selected
10 from: 10 from: sodium R-beta-hydroxybutyrate; sodium R-beta-hydroxybutyrate;
potassiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate;
magnesium magnesium R-beta-hydroxybutyrate; R-beta-hydroxybutyrate;
15 15 sodium S-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate;
potassiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calcium S-beta-hydroxybutyrate;and calcium S-beta-hydroxybutyrate; and magnesium magnesium S-beta-hydroxybutyrate; S-beta-hydroxybutyrate;
whereinthe wherein thecomposition composition comprises comprises 75% 75% to 99.9% to 99.9% by equivalents by molar molar equivalents of the racemic of the racemic
20 mixture ?O mixture of beta-hydroxybutyrate of beta-hydroxybutyrate saltssalts andto25% and 25% 0.1%toby0.1% molarby molar equivalents equivalents of the of the racemic racemic mixture of mixture of beta-hydroxybutyric beta-hydroxybutyricacids, acids, wherein thecomposition wherein the composition is provided is provided as or as in or in a tablet, a tablet, capsule, capsule, powder, powder, food product, food product, food additive, food additive,
flavored beverage, flavored beverage, vitamin vitamin fortified fortified beverage, beverage, non-alcoholic non-alcoholic beverage, beverage, flavoredadditive, flavored beverage beverage additive, vitamin fortifiedbeverage vitamin fortified beverage additive, additive, non-alcoholic non-alcoholic beverage beverage additive,additive, candy, candy, sucker, sucker,food pastille, pastille, food 25 supplement, 25 supplement, flavored flavored mouth mouth spray, spray, or suppository. or suppository.
[0020C]
[0020C] In In some some embodiments, embodiments, there there is disclosed is disclosed a racemic a racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid composition salt-acid composition for for increasing increasing ketone ketone level level in in a subject, a subject, comprising: comprising:
aa dietetically or pharmaceutically dietetically or pharmaceutically acceptable acceptable carrier carrier selected selected from from the theconsisting group group consisting of of tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified
30 30 beverage, non-alcoholic beverage, non-alcoholicbeverage, beverage,flavored flavoredbeverage beverageadditive, additive,vitamin vitaminfortified fortified beverage beverage
-Page -Page 6A- 6A- additive, non-alcoholic beverage additive, candy,candy, sucker,sucker, pastille, food supplement, 16 Apr 2025 2020221569 16 Apr 2025 additive, non-alcoholic beverage additive, pastille, food supplement, flavored mouth flavored spray,and mouth spray, andsuppository; suppository; aa racemic mixtureof racemic mixture of beta-hydroxybutyric beta-hydroxybutyricacids acidscontaining containing50% 50%by by enantiomeric enantiomeric equivalents equivalents of of R-beta-hydroxybutyric acidand R-beta-hydroxybutyric acid and50% 50%by by enantiomeric enantiomeric equivalents equivalents of S- of S-
5 5 beta-hydroxybutyric acid; and beta-hydroxybutyric acid; and aa racemic mixtureof racemic mixture of beta-hydroxybutyrate beta-hydroxybutyratesalts saltscontaining containing50% 50%byby enantiomeric enantiomeric
equivalents of of one one or or more R-beta-hydroxybutyrate saltsand and50% 50%by by enantiomeric 2020221569
equivalents more R-beta-hydroxybutyrate salts enantiomeric
equivalents of equivalents of one one or or more S-beta-hydroxybutyratesalts, more S-beta-hydroxybutyrate salts, wherein whereinthe thebeta- beta- hydroxybutyratesalts hydroxybutyrate salts are are selected selected from: from:
10 10 sodium R-beta-hydroxybutyrate; sodium R-beta-hydroxybutyrate;
potassiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; magnesium magnesium R-beta-hydroxybutyrate; R-beta-hydroxybutyrate;
sodium S-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate;
15 15 potassiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calcium S-beta-hydroxybutyrate; calcium S-beta-hydroxybutyrate;and and magnesium magnesium S-beta-hydroxybutyrate, S-beta-hydroxybutyrate,
whereinthe wherein the composition compositioncomprises comprises 75% 75% to 99.9% to 99.9% by molar by molar equivalents equivalents of racemic of the the racemic mixture of mixture of beta-hydroxybutyrate beta-hydroxybutyratesalts salts and and25% 25%toto0.1% 0.1%by by molar molar equivalents equivalents of of thethe
20 20 racemic mixture racemic mixtureofofbeta-hydroxybutyric beta-hydroxybutyricacids. acids.
[0020D]
[0020D] In In some some embodiments, embodiments, therethere is disclosed is disclosed a kit a kit forfor administering administering ketone ketone bodies bodies to to a a
subject, subject, comprising: comprising:
the racemic the R,S-beta-hydroxybutyratemixed racemic R,S-beta-hydroxybutyrate mixed salt-acida acomposition salt-acid composition according according to the to the disclosure; disclosure;
aa container container in in which which the the composition is placed; composition is placed; and and
25 a measuring 25 a measuring device device configured configured to hold to hold therein therein a unit a unit dose, dose, or or fractionthereof, fraction thereof,ofofthe the composition, composition, whereinthe wherein the unit unit dose of the dose of the composition contains about composition contains about0.5 0.5 gg to to about about 25 g of 25 g of R,S-beta- R,S-beta-
hydroxybutyratemixed hydroxybutyrate mixed salt-acidcompounds. salt-acid compounds.
[0020E]
[0020E] In In some some embodiments, embodiments, therethere is disclosed is disclosed a method a method for increasing for increasing ketone ketone bodybody levellevel in ain a
subject, comprising subject, comprising administering administering to a subject to a subject in needinthereof need thereof a nutritionally a nutritionally or pharmaceutically or pharmaceutically
30 effective 30 effective amount amount of aofcomposition a composition according according to the to the disclosure, disclosure, wherein wherein
increasing ketone increasing ketone body body level level in subject in the the subject results results in oneinorone moreorofmore of appetite appetite suppression, suppression,
-Page 6B- -Page 6B- weight loss, fat fat loss, loss,reduced reduced blood blood glucose level, improved mentalalertness, alertness,anxiolytic anxiolyticeffects effects 16 Apr 2025 2020221569 16 Apr 2025 weight loss, glucose level, improved mental
(anti-anxiety), (anti-anxiety), faster fasterreaction reaction time, time, increased physicalenergy, increased physical energy,improved improved cognitive cognitive function, function,
reduction in traumatic reduction in traumatic brain brain injury, injury, reduction reduction in in effect effect of of diabetes, diabetes, improvement improvementof of neurologicaldisorder, neurological disorder,reduction reduction of cancer, of cancer, reduction reduction of inflammation, of inflammation, anti-aging, anti-aging, anti- anti- 5 5 glycation, glycation, reduction in epileptic reduction in epileptic seizure, seizure,improved mood,increased improved mood, increased strength,increased strength, increased muscle muscle
mass, or mass, or improved improvedbody body composition; composition; and and S-beta-hydroxybutyrate components in the composition cause at least one of:of: 2020221569
S-beta-hydroxybutyrate components in the composition cause at least one
increased endogenousproduction increased endogenous production ofof R-beta-hydroxybutyrate R-beta-hydroxybutyrate and and acetoacetate; acetoacetate;
endogenous conversion endogenous conversion of of theS-beta-hydroxybutyrate the S-beta-hydroxybutyrate components components into into one or one or
10 10 both of both of R-beta-hydroxybutyrate andacetoacetate; R-beta-hydroxybutyrate and acetoacetate; endogenous conversion endogenous conversion of of theS-beta-hydroxybutyrate the S-beta-hydroxybutyrate components components into into fatty fatty acids acids
and sterols; and sterols;
prolongedketosis; prolonged ketosis; metabolismofofthe metabolism theS-beta-hydroxybutyrate S-beta-hydroxybutyrate components components independent independent of conversion of conversion
15 15 to R-beta-hydroxybutyrate to and/oracetoacetate; R-beta-hydroxybutyrate and/or acetoacetate; increased fetal development; increased fetal development;
increased increased growth years; growth years;
reduced endogenous reduced endogenous production production of of acetone acetone during during ketosis; ketosis;
signaling signaling by by the the S-beta-hydroxybutyrate components S-beta-hydroxybutyrate components that that modulates modulates metabolism metabolism
20 ?O of of R-beta-hydroxybutyrate andglucose; R-beta-hydroxybutyrate and glucose; antioxidant activity;oror antioxidant activity;
production of production of acetyl-CoA. acetyl-CoA.
[0021] Additional
[0021] Additional features features and advantages and advantages will be will be setinforth set forth in the part in partdescription in the description that follows, that follows,
and inpart and in partwill willbebeobvious obviousfromfrom the description, the description, or mayor bemay be learned learned by ofpractice by practice the of the 25 25 embodiments embodiments disclosed disclosed herein.ItItis herein. is to to be be understood that both understood that both the the foregoing foregoing brief brief summary and summary and
the following detailed description are exemplary and explanatory only and are not restrictive of the following detailed description are exemplary and explanatory only and are not restrictive of
the embodiments the disclosedherein embodiments disclosed hereinororasasclaimed. claimed.
[0022] Figure1A1Aillustrates
[0022] Figure illustrates higher higher levels levels of of the the amount amountofofbeta-hydroxybutyrate beta-hydroxybutyrate administered administered
30 when 30 when using using a “stacked” a "stacked" dose dose of atofleast at least twotwo different different forms forms of of racemic racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate
as as compared tosingle compared to single forms formsofof racemic racemicR,S-beta-hydroxybutyrate; R,S-beta-hydroxybutyrate;
-Page 6C- -Page 6C-
[0023] Figure1B1Billustrates illustrates expected expectedrelative relativerates ratesofofundesirable undesirableside-effects side-effectsresulting resultingfrom from 16 Apr 2025 2020221569 16 Apr 2025
[0023] Figure
treatment with treatment with various various formulations formulations of of beta-hydroxybutyrate, wherea a"double beta-hydroxybutyrate,where “doublestack" stack”(i.e., (i.e., double double
racemic stack) racemic stack) formulation formulationcomprising comprising1) 1) freeR,S-beta-hydroxybutyric free R,S-beta-hydroxybutyric acids acids and and (2) R,S-beta- (2) R,S-beta-
hydroxybutyrate salts and a “triple stack” (i.e., triple racemic stack) formulation further comprising hydroxybutyrate salts and a "triple stack" (i.e., triple racemic stack) formulation further comprising
5 5 R,S-beta-hydroxybutyric esters on top of the double stack are expected to allow for administration R,S-beta-hydroxybutyric esters on top of the double stack are expected to allow for administration
of greater amounts of greater amounts ofofbeta-hydroxybutyrate beta-hydroxybutyrate and/or and/or reduced reduced occurrences occurrences or intensities or intensities of side- of side-
effects effects as ascompared to administering single forms of beta-hydroxybutyrate; beta-hydroxybutyrate; 2020221569
compared to administering single forms of
[0024] Figure22 compares
[0024] Figure comparesexpected expected releaseprofiles release profilesofofR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate stack stack
compositions compositions to to free free acid, acid, salt, salt, andand ester ester single single forms forms andanalso and also an R-beta- R-beta-
-Page 6D- -Page 6D- hydroxybutyrate hydroxybutyrate stack, stack, illustrating illustrating that that stacked stacked R,S-compositions R,S-compositions provide provide an an overall overall release profile that is extended and has a larger area under the curve (AUC); and
[0025] Figure 3 illustrates expected relative rates of lipolysis and/or fat oxidation
resulting from treatment with a combination weight loss supplement including a beta-
hydroxybutyrate component in combination with another weight loss supplement, and
showing total amount of lipolysis and/or fat oxidation (area under the curve) is higher for
a combination supplement using racemic R,S-beta-hydroxybutyrate components as
compared to otherwise similar combination supplements/drugs using beta-
hydroxybutyrate components enriched in R-beta-hydroxybutyrate or S-beta- hydroxybutyrate.
DETAILED DESCRIPTION I. Definitions
[0026] The compound "beta-hydroxybutyrate," also known as B-hydroxybutyrate, ß-hydroxybutyrate, 3-
hydroxybutyrate, BHB, ßHB, or BHB, is the deprotonated form of beta-hydroxybutyric acid,
which is a hydroxycarboxylic acid having the general formula CH3CHOHCHH. CHCHOHCHCOOH.
The deprotonated form present at typical biological pH levels is CH3CHOCHOO CHCHOHCHCOO.
The general chemical structure shown below represents beta-hydroxybutyrate compounds that may be utilized in the disclosed compositions:
HO O-X o-x where,
X X can can be behydrogen, hydrogen,metal ion,ion, metal aminoamino cationcation such assuch fromas an from amino an acid, alkyl, amino acid, alkyl,
alkenyl, aryl, or acyl.
[0027] When X is a hydrogen, the compound is beta-hydroxybutyric acid. When X is a
metal ion or an amino cation, the compounds is a beta-hydroxybutyrate salt. When X is
alkyl, alkenyl, aryl, or acyl, the compounds is a beta-hydroxybutyrate ester. The
foregoing compounds can be in any desired physical form, such as crystalline, powder,
solid, solid,liquid, liquid,solution, suspension, solution, or gel.or gel. suspension,
[0028] The term "racemic R,S-beta-hydroxybutyrate" means there are enantiomerically
equivalent amounts (50:50) of total R- and S-beta-hydroxybutyrate in the composition.
The terms "racemic R,S-beta-hydroxybutyrate salt" and "racemic R,S-beta-
hydroxybutyrate salts" mean there are enantiomerically equivalent amounts (50:50) of
total R- and S-beta-hydroxybutyrate salts in the composition. The term "racemic R,S-
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WO wo 2020/167690 PCT/US2020/017552
beta-hydroxybutyric acid" means there are enantiomerically equivalent amounts (50:50)
of R- and S-beta-hydroxybutyric acids in the composition. The terms "racemic R,S-beta-
hydroxybutyrate ester" and "racemic R,S-beta-hydroxybutyrate esters" mean there are
enantiomerically equivalent amounts (50:50) of total R- and S- beta-hydroxybutyrate
esters in the composition.
[0029] The term "R,S-beta-hydroxybutyrate mixed salt-acid composition" means there
are enantiomerically equivalent amounts of one or more R-beta-hydroxybutyrate salts
and one or more S-beta-hydroxybutyrate salts in the composition, and there are
enantiomerically equivalent amounts (50:50) of free R-beta-hydroxybutyric acid and free
S-beta-hydroxybutyric S-beta-hydroxybutyric acid acid in in the the composition. composition.
[0030] The term "R,S-beta-hydroxybutyrate salt" does not mean or imply any particular
physical state, such as a crystalline, powder, other solid form, dissolved in water to form
a liquid solution, dispersed in a liquid to form a suspension, or gel. A salt can be formed
in solution, such as by at least partially neutralizing beta-hydroxybutyric acid with a
strong or weak base, such as an alkali or alkaline earth metal hydroxide, carbonate, or
bicarbonate, basic amino acid, and the like.
[0031] The term "free beta-hydroxybutyric acid" means the sum of non-deprotonated
and deprotonated beta-hydroxybutyric acid molecules. A deprotonated beta- hydroxybutyric acid molecule generally means a molecule that has released a proton to
form a hydronium ion (H3O+) andaabeta-hydroxybutyrate (HO+) and beta-hydroxybutyrateanion anion(e.g., (e.g.,dissolved dissolvedin in
water).
[0032] Free beta-hydroxybutyric acid molecules are typically not deprotonated to any
significant degree when contained in a beta-hydroxybutyrate mixed salt-acid
composition in dry powder or other solid form. In such cases, the fractional amount of
free beta-hydroxybutyric acid in a beta-hydroxybutyrate mixed salt-acid composition on
a weight basis is the weight of free beta-hydroxybutyric acid divided by the combined
weight of free beta-hydroxybutyric acid and beta-hydroxybutyrate salt(s). On a molar
basis, the fractional amount of free beta-hydroxybutyric acid in an beta-hydroxybutyrate
mixed salt-acid composition are the molar equivalents of free beta-hydroxybutyric acid
divided by the sum of molar equivalents of free beta-hydroxybutyric acid and beta-
hydroxybutyrate anions provided by the beta-hydroxybutyrate salt(s).
[0033] When dissolved in water, a portion of the beta-hydroxybutyric acid will typically
dissociate into beta-hydroxybutyrate anions and hydronium ions (H3O+). As aa result, (HO+). As result,
beta-hydroxybutyric acid molecules can exchange protons and cations with dissolved
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WO wo 2020/167690 PCT/US2020/017552
beta-hydroxybutyrate salts. For purposes of defining the relative amounts of beta-
hydroxybutyric acid and beta-hydroxybutyrate salt(s) in a beta-hydroxybutyrate mixed
salt-acid composition, dissociation of beta-hydroxybutyric acid molecules and the
exchange of protons and cations is not understood as changing the molar ratio of free
beta-hydroxybutyric acid relative to beta-hydroxybutyrate anions from the beta-
hydroxybutyrate hydroxybutyrate salt(s). salt(s). The The total total quantity quantity of of free free beta-hydroxybutyric beta-hydroxybutyric acid acid molecules molecules in in
solution is the sum of dissolved beta-hydroxybutyric acid molecules that are not
deprotonated and beta-hydroxybutyrate anions formed by deprotonation of beta-
hydroxybutyric acid molecules.
[0034] Stated another way, the total molar equivalents of beta-hydroxybutyric acid in
solution, whether or not deprotonated, is understood to be the difference between (i) the
sum of molar equivalents of non-deprotonated beta-hydroxybutyric acid molecules and
total molar equivalents of beta-hydroxybutyrate anions in solution (from all sources) and
(ii) the total molar equivalents of cationic charge provided by cations from the beta-
hydroxybutyrate salt compounds (which equals the total molar equivalents of beta-
hydroxybutyrate anions provided by the beta-hydroxybutyrate salt(s)). Alkali metal
cations such as sodium and potassium provide 1 mole of cationic charge per mole of
metal cations. Alkaline earth metal cations such as magnesium and calcium, on the other
hand, provide 2 moles of cationic charge per mole of metal cations. 1 mole of
deprotonated beta-hydroxybutyric acid molecules provide 1 mole of anionic charge and
one mole of cationic charge.
[0035] In view of the foregoing, the molar fraction of beta-hydroxybutyric acid in
solution in relation to total moles of beta-hydroxybutyrate molecules from the beta-
hydroxybutyrate mixed salt-acid composition in solution is [(i)-(ii) (i)], and ÷ (i)], the and molar the molar
fraction of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate salt(s)) in
solution is [(ii) (i)]. Multiplying ÷ (i)]. the Multiplying molar the fraction molar ofof fraction each byby each 100 gives 100 the gives percentage the percentage
of each in solution.
[0036] By way of example, if 100 molar equivalents of beta-hydroxybutyrate mixed salt-
acid composition in a dry powdered state contained 5% of free non-deprotonated beta-
hydroxybutyric acid and 95% beta-hydroxybutyrate salt(s) on a molar basis, there would
be essentially 5 molar equivalents of beta-hydroxybutyric acid molecules and 95 molar
equivalents of beta-hydroxybutyrate anions. When there is sufficient water to dissolve
the beta-hydroxybutyrate salt(s), and if a portion of the beta-hydroxybutyric acid
molecules were deprotonated, the molar equivalents of non-deprotonated beta-
- Page 9 -
PCT/US2020/017552
hydroxybutyric acid would be less than 5, and the molar equivalents of beta-
hydroxybutyrate anions would be greater than 95. The extent of deprotonation of beta-
hydroxybutyric acid in solution is related to pH.
[0037] Whether beta-hydroxybutyrate is the R- or S-enantiomer depends on the
tetrahedral orientation of the hydroxy on the 3-carbon (beta-carbon) in relationship to the
planar carboxyl group.
[0038] Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, which is the
endogenous form produced by mammals, can be utilized by a patient's body as a fuel
source during instances of low glucose levels in the subject or when a patient's body is
supplemented with a usable form of beta-hydroxybutyrate. Beta-hydroxybutyrate is
commonly referred to as a "ketone body."
[0039] As used herein, a "ketogenic composition" is formulated to increase ketone body
level in a subject, including inducing and/or sustaining a state of elevated ketone bodies
at a desired level, such as ketosis, in a subject to which it is administered administered.
[0040] As used herein, "subject" or "patient" refers to members of the animal kingdom,
including mammals, such as but not limited to, humans and other primates; rodents, fish,
reptiles, and birds. The subject may be any animal requiring therapy, treatment, or
prophylaxis, or any animal suspected of requiring therapy, treatment, or prophylaxis.
Prophylaxis means that regiment is undertaken to prevent a possible occurrence, such as
where a high glucose or diabetes is identified. "Patient" and "subject" are used
interchangeably herein.
[0041] "Ketosis" as used herein refers to a subject having blood ketone levels, including
both enantiomers of beta-hydroxybutyrate, acetoacetate and acetone, within the range of
about 0.5 mmol/L and about 16 mmol/L in a subject. Ketosis may improve mitochondrial
function, decrease reactive oxygen species production, reduce inflammation and increase
the activity of neurotrophic factors. "Keto-adaptation" as used herein refers to prolonged
nutritional ketosis (>1 week) to achieve a sustained nonpathological "mild ketosis" or
"therapeutic ketosis."
[0042] In some cases, "elevated ketone body level" may not mean that a subject is in a
state of "clinical ketosis" but nevertheless has an elevated supply of ketones for
producing energy and/or for carrying out other beneficial effects of ketone body
metabolism and signaling. For example, a subject that is "ketone adapted" may not
necessarily have elevated blood serum levels of ketone bodies but rather is able to utilize
available ketone bodies more rapidly compared to a subject that is not "ketone adapted."
- Page 10 -
In such case, "elevated ketone body level" can refer to the total quantity and/or rate of
ketone bodies being utilized by the subject rather than blood plasma levels per se.
[0043] The term "administration" or "administering" is used herein to describe the
process in which the disclosed compositions are delivered to a subject. The composition
may be administered in various ways including oral, intragastric, and parenteral
(referring to intravenous and intra-arterial and other appropriate parenteral routes),
among others.
[0044] The term "combination supplement" is used herein to describe the combination of
a beta-hydroxybutyrate component with one or more other supplements and/or drugs.
The beta-hydroxybutyrate component and the one or more other supplements and/or
drugs may be directly combined, such as by mixing together in the same tablet, capsule,
mixed powder, or other dosage form, or such as by placing the separate components in
the same packaging even if not directly mixed. In other embodiments, however, the
separate components need not necessarily be directly combined prior to administration in
order to fall within the scope of this disclosure. For example, the separate components
may be administered to a subject separately but close enough in time (e.g., within about
8, 6, 4, 2, 1, or 0.5 hours of each other) to be considered co-administered and thus part of
a "combination supplement."
II. II. Racemic R,S-Beta-Hydroxybutyrate Mixed Salt-Acid Compositions
[0045] Compositions for increasing ketone body level in a subject, including promoting
and/or sustaining ketosis, comprise racemic R,S-beta-hydroxybutyrate mixed salt-acid
compositions, including (1) 50% by enantiomeric equivalents of one or more R-beta-
hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-
hydroxybutyrate salts and (2) 50% by enantiomeric equivalents of R-beta-
hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta-hydroxybutyric
acid. The composition may optionally include 50% by enantiomeric equivalents of one
or more R-beta-hy droxybutyrate esters R-beta-hydroxybutyrate esters and and 50% 50% by by enantiomeric enantiomeric equivalents equivalents of of one one or or
more S-beta-hydroxybutyrate esters. A racemic mixture of R,S-beta-hydroxybutyrate
mixed salt-acid components can provide synergistic effects, such when used in
combination with other components. In such case, the combined salt and acid forms of
R,S-beta-hydroxybutyrate have acceptable pH and taste. R,S-beta-hydroxybutyrate
mixed salt-acid compositions have substantial advantages over racemic R,S-beta-
hydroxybutyrate salts and esters, including increased absorption rate, increased
bioavailability, lower electrolyte load, ease of manufacture, significantly improved taste,
- Page 11 - and reduced need for citric acid or other edible acids to obtain a composition with neutral or acidic pH.
[0046] In some embodiments, the racemic R,S-beta-hydroxybutyrate R,S-beta-hy droxybutyratemixed mixedsalt-acid salt-acid
composition contains less than 100% of racemic R,S-beta-hydroxybutyrate salts and
greater than 0% of free racemic R,S-beta-hydroxybutyric acids. Racemic R,S-beta-
hydroxybutyrate mixed salt-acid compositions may contain, on a molar basis, up to
99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%, 99.3%, 99.2%, 99.1%, 99%, 98.8%,
98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%, 97.5%, 97.25%, or 97%, and at least
75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or 97%, of total racemic R,S-beta-
hydroxybutyrate salts and at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,
0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%, 1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%, and less
than 25%, 20%, 15%, 10%, 8%, 6%, 5%, 4%, or 3%, of total free racemic R,S-beta-
hydroxybutyric acids. The foregoing percentages are expressed on a molar basis (e.g.,
moles of free R,S-beta-hydroxybutyric acids relative to total moles of R,S-beta-
hydroxybutyrate hydroxybutyrate compounds compounds in in both both salt salt and and acid acid forms). forms).
[0047] The racemic mixture of R-beta-hydroxybutyrate mixed salt-acid components and
S-beta-hydroxybutyrate mixed salt-acid components contains equivalent amounts of the
R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer, enantiomer, the the endogenous endogenous form form produced produced byby a a mammal, mammal, and and
the S-beta-hydroxybutyrate enantiomer, which is not produced or found naturally in
mammals, in order to provide enhanced ketogenic effects not possible with either of the
enantiomers delivered alone or in enriched form.
[0048] For example, the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer isis endogenously endogenously produced produced
by a mammal during ketosis, and thus administering the R-beta-hydroxybutyrate mixed
salt-acid components to a subject provides an additional quantity and/or increased blood
plasma level that can be relatively immediately utilized by the body, such as for
producing energy (e.g., as an alternative energy source to glucose). The presence of the
S-beta-hydroxybutyrate mixed salt-acid components can modulate this effect in order to
provide, for example, a more controlled, gradual, and/or extended ketogenic effect
compared to a composition enriched with the R-beta-hydroxybutyrate mixed salt-acid
components.
[0049] By way of further example, a racemic R,S-beta-hydroxybutyrate mixed salt-acid
composition can beneficially provide a relatively rapid boost to blood ketone body
levels, primarily by way of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer components, components, inin
addition to a relatively more extended, sustained increase to blood ketone body levels
- Page 12 - primarily by way of the S-beta-hydroxybutyrate enantiomer components. Such compositions are thus capable of effectively and relatively rapidly aiding a subject in in inducing ketosis, while simultaneously providing for sustained and prolonged delivery of ketone bodies to the blood stream, wherein the R-beta-hydroxybutyrate and S-beta- hydroxybutyrate components together provide synergistic ketogenic benefits to a subject.
[0050] Contrary to compositions that deliberately minimize or eliminate S-beta-
hydroxybutyrate, the racemic R,S-beta-hydroxybutyrate mixed salt-acid composition
contains an equivalent quantity of the S-beta-hydroxybutyrate enantiomer, which is not
endogenously produced by a mammal, in order to produce one or more desired effects in
the mammal. For example, administering S-beta-hydroxybutyrate mixed salt-acid
components along with R-beta-hydroxybutyrate mixed salt-acid components can result in
at least one of: (1) increased endogenous production of R-beta-hy droxy butyrate R-beta-hydroxybutyrate and and
acetoacetate; (2) endogenous conversion of the S-beta-hydroxybutyrate components into
one or both of R-beta-hydroxybutyrate and acetoacetate; (3) endogenous conversion of
the S-beta-hydroxybutyrate components into fatty acids and sterols; (4) prolonged
ketosis; (5) metabolism of the S-beta-hydroxybutyrate components independent of
conversion to R-beta-hy droxybutyrateand/or R-beta-hydroxybutyrate and/oracetoacetate; acetoacetate;(6) (6)increased increasedfetal fetal
development; (7) increased growth years; (8) reduced endogenous production of acetone
during ketosis; (9) signaling by the S-beta-hydroxybutyrate that modulates metabolism
of R-beta-hydroxybutyrate and glucose; (10) antioxidant activity; and (11) production of
acetyl-CoA.
[0051] The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition can be used,
for example, to produce one or more desired effects in the subject, including but not
limited to, appetite suppression, weight loss, fat loss, reduced blood glucose level,
improved mental alertness, increased physical energy, improved cognitive function,
reduction in traumatic brain injury, reduction in effect of diabetes, improvement of
neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, anti-
glycation, reduction in epileptic seizer, improved mood, increased strength, increased
muscle mass, or improved body composition.
[0052] In some embodiments, the racemic R,S-beta-hydroxybutyrate R,S-beta-hy droxybutyratemixed mixedsalt-acid salt-acid
compositions may include or be combined with a carrier, such as a dietetically or
pharmaceutically acceptable carrier. Examples carrier or forms of the composition
include powders, liquids, tablets, capsules, food products, food additives, beverages,
vitamin fortified beverages, beverage additives, candies, suckers, pastilles, food
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supplements, sprays, injectables, and suppositories.
[0053] Examples of R,S-beta-hydroxybutyrate salts include salts of alkali metals,
alkaline earth metals, transition metals, amino acids, or metabolites of amino acids.
Examples include lithium salts, sodium salts, potassium salts, magnesium salts, calcium
salts, zinc salts, iron salts (as iron II and/or iron III), chromium salts, manganese salts,
cobalt salts, copper salts, molybdenum salts, selenium salts, arginine salts, lysine salts,
leucine salts, isoleucine salts, histidine salts, ornithine salts, citrulline salts, glutamine
salts, and creatine salts.
[0054] Racemic R,S-beta-hydroxybutyrate mixed salt-acid compositions may optionally
include racemic R,S-beta-hydroxybutyrate esters, such as mono-, di-, tri-, oligo-, and
polyesters. Examples include mono-ester of ethanol, mono-ester of 1-propanol, mono-
ester of 1,2-propanediol, di-ester of 1,2-propanediol, mono-ester of 1,3-propanediol, di-
ester of 1,3-propanediol, mono-ester of S-, R-, or S-R-1,3-butanediol, di-ester of S-, R-,
or S-R-1,3-butanediol, mono-ester of glycerin, (3S)-hydroxybuty] (3S)-hydroxybutyl (3S)-hydroxybutyrate
mono-ester, (3R)-hydroxybutyl (3S)-hydroxybutyrate, mono-ester, di-ester of glycerin,
tri-ester of glycerin, ester of acetoacetate, dimers, trimers, oligomers, and polyesters
containing repeating units of beta-hydroxybutyrate. beta-hydroxybutyrate, and complex oligomers or polymers
of BHB and one or more other hydroxy-carboxylic acids, such as lactic acid, citric acid,
acetoacetic acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, and malic acid,
and/or beta-hydroxybutyrate and or one or more diols, such as 1,3-propanediol and 1,3-
butanediol, one or more polyacids, such as tartaric acid, citric acid, malic acid, succinic
acid, and fumaric acid, and short chain fatty acids, such as butyric acid, valeric acid, or
caproic acid.
[0055] In some embodiments, the composition may further include or be combined with
at least one short chain fatty acid, or a mono-, di- or triglyceride of the at least one short
chain fatty acid, wherein the short chain fatty acid has less than 6 carbons. Example short
chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric
acid, and isovaleric acid. An example short chain triglyceride is tributyrin. Such
molecules can provide protection to the gut and improve microbiome health.
[0056] The composition may include or be combined with at least one medium chain
fatty acid, or a mono-, di- or triglyceride of the at least one medium chain fatty acid,
wherein the medium chain fatty acid has from 6 to 12 carbons, preferably from 8 to 10
carbons. Example medium chain fatty acids are caproic acid, caprylic acid, capric acid,
and lauric acid. Medium chain triglycerides (MCT), medium chain fatty acids, and
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mono- and di-glycerides are ketone body precursors that can provide an additional
source for the production of ketone bodies independent of R-beta-hydroxybutyrate.
[0057] The composition may include or be combined with at least one long chain fatty
acid, or a mono-, di- or triglyceride of the at least one long chain fatty acid, having more
than 12 carbons. Examples of long-chain fatty acids include myristic acid, palmitic acid,
stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, omega-3 fatty
acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids.
[0058] Examples and sources of the medium chain fatty acid, or an ester thereof such as
a medium chain triglyceride, include coconut oil, coconut milk powder, fractionated
coconut oil, palm oil, palm kernel oil, caprylic acid, capric acid, isolated medium chain
fatty acids, such as isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid,
medium chain triglycerides either purified or in natural form such as coconut oil, and
ester derivatives of the medium chain fatty acids ethoxylated triglyceride, enone
triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives,
diglyceride derivatives, and triglyceride derivatives, and salts of the medium chain
triglycerides. Ester derivatives optionally include alkyl ester derivatives, such as methyl,
ethyl, propyl, butyl, hexyl, etc.
[0059]
[0059] The Theadministration of aof administration racemic mixture a racemic of R-beta-hy mixture droxy butyrate mixed salt- of R-beta-hydroxybutyrate mixed salt-
acid components and S-beta-hydroxybutyrate mixed salt-acid components results in a
dual effect providing both: (1) an initial and relatively immediate elevated blood level of
ketone bodies; and (2) a later and relatively extended elevated blood level of ketone
bodies, bodies,thereby therebyexploiting the the exploiting metabolic and physiological metabolic advantages and physiological of (1) quickly advantages of (1) quickly
induced and (2) temporally sustained ketosis.
[0060] Raising the levels of ketone bodies in the blood through exogenous
supplementation provides a subject with greater flexibility in diet options as compared to
methods that aim to induce and sustain ketosis based on diet alone (e.g., based on fasting
and/or limited carbohydrate intake). For example, a subject that has been administered an
appropriate amount of a racemic mixture of R-beta-hydroxybutyrate mixed salt-acid
components and S-beta-hydroxybutyrate mixed salt-acid components will be able to eat
an occasional carbohydrate or sugar-based food without jeopardizing the ketogenic state
and shifting back into a glucose-based metabolic state. Further, such administration
facilitates easier transitioning into a ketogenic state while reducing or eliminating the
detrimental effects typically associated with entering ketosis.
[0061] In some embodiments, a ketogenic composition additionally includes a
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therapeutically effective amount of vitamin D3. Vitamin DD3 D. Vitamin isis believed believed toto work work inin
conjunction with magnesium and calcium to promote good bone health and to prevent
undesirable calcification of soft tissues. In preferred embodiments, vitamin D3 is D is
included in an amount such that an average daily dose of the ketogenic composition
includes about 200 IU ("International Units") to about 8000 IU, or about 400 IU to about
4000 4000 IU, IU,ororabout 600600 about IU to IU about 3000 3000 to about IU of IU vitamin D3. In some of vitamin embodiments, D. In vitamin some embodiments, vitamin
D3 isincluded D is includedin inan anamount amountsuch suchthat thatan anaverage averagedaily dailydose doseof ofthe theketogenic ketogeniccomposition composition
includes about 5 ug µg to about 200 ug, µg, or about 10 ug µg to about 100 ug, µg, or about 15 ug µg to
about about 75 75ugµgofof vitamin D3. D. vitamin
[0062] Some embodiments also include one or more additional ketone precursors or
supplements. These additional ketone precursors or supplements might include
acetoacetate, ketone esters, and/or other compounds that cause a rise in blood ketone
levels without adding more electrolytes to the bloodstream. Acetoacetate can be provided
in salt form, ester form, acid form, and combinations thereof. Other additives include
metabolites that enhance the effect or transport of ketone bodies into mitochondria,
caffeine, theobromine, and nootropics, such as L-alpha glycerylphosphorylcholine
("alpha GPC").
[0063] The composition may include flavoring agents that help mask the occasionally
poor taste of beta-hydroxybutyrate compounds (particularly when provided in a non-salt
form). These include essential oils, such as peppermint, natural and artificial sweeteners,
and other flavorants known in the art.
[0064] In some embodiments, ketogenic compositions may further include one or more
additional components configured to lower the hygroscopicity of the composition. For
example, various anticaking agents, flow agents, and/or moisture absorbers, in types and
amounts that are safe for consumption, may be included. Such additional components
may include one or more of an aluminosilicate, ferrocyanide, carbonate or bicarbonate
salt, silicate (e.g., sodium or calcium silicate), silica, phosphate salt (e.g., di- or
tricalcium phosphate), talc, powdered cellulose, calcium carbonate, and the like.
III. Stacking of Racemic R,S-Beta-Hydroxybutyrate Compounds
[0065] As described above, the racemic R,S-beta-hydroxybutyrate R,S-beta-hy droxybutyratemixed mixedsalt-acid salt-acid
compositions described herein may be provided in three general forms: (1) racemic R,S-
beta-hydroxybutyrate salt(s), (2) racemic R,S-beta-hydroxybutyric acid, and optionally
(3) racemic R,S-beta-hydroxybutyrate ester(s). The compositions described herein may
be provided in "stacked" mixtures combining at least salt and acid forms and optionally
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ester forms
[0066] Each of the different forms has its own properties and its own potential benefits
and limitations. For example, ester forms of beta-hydroxybutyrate typically have poor
organoleptic properties relative to the other forms of beta-hydroxybutyrate. That is, ester
forms of beta-hydroxybutyrate are often described as having a pungent taste and/or
smell.
[0067] Salt forms of racemic R,S-beta-hydroxybutyrate are generally considered to taste
better than ester forms. However, administration of clinically or dietetically effective
doses of racemic R,S-beta-hydroxybutyrate in salt form inherently requires
administration of relatively high levels of the corresponding cations. Sodium, for
example, is often used as the cation in beta-hydroxybutyrate salts, and high levels of
sodium have well-known negative health effects. Although different beta- hydroxybutyrate salts having different cations may be mixed to dilute the impact of a
single cation, it can still be difficult to provide effective amounts of beta-
hydroxybutyrate without upsetting the electrolyte balance in the subject/patient.
[0068] The free acid form of racemic R,S-beta-hydroxybutyrate (i.e., racemic R,S-beta-
hydroxybutyric acid) hydroxybutyric is is acid) therefore utilized therefore to form utilized tothe mixed form thesalt-acid compositions. mixed salt-acid compositions.
Because beta-hydroxybutyric acid has a pKa of 4.70, it deprotonates and produces H+ at
physiological pH. The resulting excess acidity can cause undesirable side effects
including causing or aggravating gastrointestinal issues such as ulcers or reflux.
[0069] Combining different forms of racemic R,S-beta-hydroxybutyrate is selected
amounts can beneficially limit the occurrence and/or severity of these undesirable side-
effects and/or can permit administration of higher doses of beta-hydroxybutyrate
compounds. For example, a beta-hydroxybutyrate stack can deliver the same amount of
beta-hydroxybutyrate as a single form without causing the same occurrence and/or
severity of side-effects. Likewise, a combined form can deliver a greater amount of beta-
hydroxybutyrate than a single form before reaching similar occurrence and/or severity of
side-effects.
[0070] This is schematically illustrated in Figures 1A and 1B. Figure 1A shows different
beta-hydroxybutyrate doses when using a single form (formulations 1-3), a double stack
(formulations 4-6), and a triple stack (formulation 7). Although individual tolerances
may vary and the illustrated doses are therefore exemplary only, a typical subject will
want to avoid excessive amounts of any single form of beta-hydroxybutyrate in order to
avoid the corresponding side effects. Accordingly, stacking different forms of beta-
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hydroxybutyrate allows for greater delivery of beta-hydroxybutyrate in a dose and/or
allows for a higher dosing frequency as compared to use of the single form. For example,
different forms of beta-hydroxybutyrate may be stacked in a single dose to allow for
greater amounts of beta-hydroxybutyrate in the dose, and/or different forms of beta-
hydroxybutyrate may be taken in different doses throughout the day to allow for greater
dosing frequency and thus higher overall daily delivery of beta-hydroxybutyrate.
[0071] Figure 1B shows expected relative severity of undesirable side-effects resulting
from treatment with various formulations of beta-hydroxybutyrate, including stacked
formulations. The triple stack formulation comprising each of 1) the salt form of beta-
hydroxybutyrate, 2) the free acid form of beta-hydroxybutyrate (i.e., beta-hydroxybutyric
acid), and 3) the ester form of beta-hydroxybutyrate is expected to allow for
administration of a greater amount of beta-hydroxybutyrate and/or to have reduced side-
effects as compared to a double stack comprising only two such forms of beta-
hydroxybutyrate. Both the triple stack (i.e., triple racemic stack) and the double stack
(i.e., double racemic stack) are likewise expected to allow for administration of a greater
amount of beta-hydroxybutyrate and/or to have reduced side-effects as compared to a
single form comprising only one form of beta-hydroxybutyrate.
[0072] In other words, for a given dose of beta-hydroxybutyrate, double and triple
racemic stacks can be formulated to cause less 1) organoleptic side-effects, 2) electrolyte
imbalance side-effects, and/or 3) acidity side-effects as compared to the single form. For
example, a single form beta-hydroxybutyrate ester may have a threshold dosage that the
typical user will not exceed because of the negative organoleptic side-effects, a single
form beta-hydroxybutyrate salt may have a threshold dosage limited by the recommended dietary limits of the electrolytes administered with the salt, and a single
form beta-hydroxybutyric acid may have a threshold dosage that the typical user will not
exceed because of the negative effects of acidity. The stacked forms of beta-
hydroxybutyrate allow for supplementation of greater amounts of beta-hydroxybutyrate
without passing any of the separate thresholds related to organoleptic, electrolyte, or
acidity side-effects.
[0073] In some embodiments, a beta-hydroxybutyrate stack includes at least two of: (i)
one or more R,S-beta-hydroxybutyrate salts; (ii) R,S-beta-hydroxybutyric acid; and (iii)
one or more beta-hydroxybutyrate esters. For example, a beta-hydroxybutyrate double
stack may include at least two of components (i), (ii), and (iii) each provided at about 2%
to about 98%, or about 5% to about 95%, or about, 10% to about 90%, or about 20% to
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about 80%, or about 30% to about 70%, or about 40% to about 60% on a molar basis of
beta-hydroxybutyrate.
[0074] An example beta-hydroxybutyrate triple stack includes a beta-hydroxybutyrate
ester ester at atabout about2% 2% to to about 96%,96%, about or about 5% to 5% or about about to 90%, or 90%, about about or 10%about to about 10%80%, to about 80%,
or about 20% to about 60% on a molar basis of beta-hydroxybutyrate, includes a beta-
hydroxybutyrate salt at about 2% to about 96%, or about 5% to about 90%, or about 10%
to about 80%, or about 20% to about 60% on a molar basis of beta-hydroxybutyrate, and
includes beta-hydroxybutyric acid at about 2% to about 96%, or about 5% to about 90%,
or about 10% to about 80%, or about 20% to about 60% on a molar basis of beta-
hydroxybutyrate. In some embodiments, a beta-hydroxybutyrate triple stack includes
each of the three forms of beta-hydroxybutyrate in substantially equal amounts on a
molar basis of beta-hydroxybutyrate.
[0075] A stacked beta-hydroxybutyrate composition may also provide a more beneficial
digestive release profile. Each of the different forms of beta-hydroxybutyrate may
interact somewhat differently upon ingestion. For example, the free acid form may be
readily delivered to the bloodstream as a usable ketone body, beta-hydroxybutyrate from
salt forms may in general take slightly longer to reach the bloodstream depending on the
solubility characteristics of the particular salt or salt mixture utilized, and beta-
hydroxybutyrate from ester forms may in general take the longest to reach the
bloodstream depending on how rapidly the ester bond undergoes hydrolysis. Thus, a
stacked beta-hydroxybutyrate formulation can be tailored to provide a more preferable
release profile, such as one that combines the benefits of more rapid onset with the
benefits of a more extended release, and/or one that provides an overall greater
pharmacokinetic area under the curve (AUC). Stacked compositions can provide for
timed delivery or availability of ketone bodies, which provides for more even blood
concentration of ketone bodies and a significantly longer delivery "tail" of exogenous
ketone bodies, such as 1-8 hours after consuming the stacked composition.
[0076] This is illustrated in Figure 2, which compares expected release profiles of keto
stack compositions (e.g., comprising the free acid and salt) to each of the free acid, salt,
and ester single forms. Because the keto stack compositions can provide more overall
exogenous ketone bodies, and because they are provided in a plurality of different forms
with different release characteristics, the overall release profile is extended and provides
a larger AUC.
[0077] Figure 2 also illustrates how a release profile may be adjusted by utilizing
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different relative amounts of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate. As
illustrated, the beta-hydroxybutyrate in the "R Stack" is comprised of R-beta-
hydroxybutyrate, while the "R/S Stack" contains a racemic mixture of R-beta-
hydroxybutyrate and S-beta-hydroxybutyrate, which flattens and extends the release
profile.
IV. Combination Supplements
[0078] The ketogenic compositions described herein may be beneficially combined with
one or more other dietetically and/or pharmaceutically acceptable supplements/drugs to
form a combination supplement. The unique properties of a racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition may beneficially enhance the combination
supplement as compared to an otherwise similar combination supplement using a beta-
hydroxybutyrate composition enriched in either R-beta-hydroxybutyrate or S-beta-
hydroxybutyrate.
[0079] For example, a composition intended to increase lipolysis and/or fat oxidation
(referred to herein as a "fat burner" component) may be combined with a racemic R,S-
beta-hydroxybutyrate component to form a combination supplement with synergistic
lipolysis and/or fat burning effects. Without being bound to any particular theory, it is
believed that the fat burner composition is more readily utilized when combined with a
racemic R,S-beta-hydroxybutyrate component as compared to when utilized without a
beta-hydroxybutyrate component. That is, the racemic R,S-beta-hydroxybutyrate
component may function to effectively "prime" the subject for more metabolically
efficient utilization of lipids. as an energy source. For example, with exogenous
supplementation of a racemic R,S-beta-hydroxybutyrate mixed salt-acid composition, a
subject is likely to ramp up the enzymes and other metabolic machinery necessary to
utilize such ketone bodies (and thus stored body fat) as an energy source. The fat burner
may therefore have enhanced pharmacokinetics and/or pharmacodynamics when co-
administered, and thus may increase lipolysis and/or fat oxidation to levels higher than if
either the beta-hydroxybutyrate component or the fat burner were administered in
isolation.
[0080] These synergistic effects of a combination supplement are believed to be more
pronounced when the beta-hydroxybutyrate component is a racemic R,S-beta-
hydroxybutyrate component as opposed to being enriched with either R-beta- hydroxybutyrate or S-beta-hydroxybutyrate. This is schematically illustrated in Figure 3.
As shown, for a combination supplement with a given beta-hydroxybutyrate dose, where
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the beta-hydroxybutyrate component is enriched in R-beta-hydroxybutyrate, the level of
fat oxidation/lipolysis is initially relatively high, but then tapers relatively rapidly. Where
the beta-hydroxybutyrate component is enriched in S-beta-hydroxy butyrate, the S-beta-hydroxybutyrate, the level level of of
fat oxidation/lipolysis is more extended in duration than the enriched R-beta-
hydroxybutyrate composition, but overall levels of fat oxidation/lipolysis remain
relatively low throughout.
[0081] On the other hand, where the beta-hydroxybutyrate component is racemic, the R-
S-beta-hy droxy butyrate beta-hydroxybutyrate components and S-beta-hydroxybutyrate components components function function toto
provide a relatively high initial level of fat oxidation/lipolysis as well as a relatively
extended duration of fat oxidation/lipolysis. Though perhaps the racemic R,S-beta-
hydroxybutyrate version does not provide an initial level of fat oxidation/lipolysis as
high as with the enriched R-beta-hydroxybutyrate version, and perhaps does not provide
a duration of fat oxidation/lipolysis as long as with the enriched S-beta-hydroxybutyrate
version, the combined effects of the R-beta-hy droxybutyratecomponents R-beta-hydroxybutyrate componentsand andS-beta- S-beta-
hydroxybutyrate components, when provided in enantiomerically equivalent proportions,
provide higher overall levels of fat oxidation/lipolysis. In other words, the area under the
curve is greater where the racemic R,S-beta-hydroxybutyrate composition is utilized in
the combination supplement as compared to the enriched R-beta-hydroxybutyrate or the
enriched S-beta-hydroxybutyrate.
[0082] The fat burner component may include one or more compounds capable of
promoting enhanced lipolysis and/or fat oxidation. For example, the fat burner
component may include green tea, green tea extract (e.g., a composition including one or
more isolated green tea catechins such as epigallocatechin gallate (EGCG)), green coffee
extract, conjugated linoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleus
forskohlii (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4-
(4-hydroxyphenyl) butan-2-one, p-hydroxybenzyl acetone), ephedrine, synephrine (e.g.,
bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin,
acetylcholine modulators and/or adenosine receptor antagonists (e.g., caffeine), nicotine,
coca leaves (e.g., teas, extracts, isolates, salts, and free bases), ursolic acid, clenbuterol,
noradrenaline reuptake inhibitors (e.g., inhibitors (e.g., hordenine, atomoxetine), 7- noradrenaline reuptake hordenine, atomoxetine), 7- oxodehydroepiandrosterone (i.e., (i.e., oxodehydroepiandrosterone 7-keto 7-keto DHEA), thyroidhormones DHEA), thyroid (e.g., hormones (e.g.,
triiodothyronine), and combinations thereof.
[0083] A combination supplement may include a beta-hydroxybutyrate component and a
component intended to enhance mental alertness, cognition, and/or mood (referred to
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herein as a "nootropic" component). As with the fat burner embodiments, it is expected
that synergistic nootropic effects are greater when the beta-hydroxybutyrate component
is a racemic mixture rather than enriched in R-beta-hydroxybutyrate or S-beta-
hydroxybutyrate.
[0084] Exemplary compounds that may be included in the nootropic component include
catecholamine precursors such as tyrosine, L-DOPA (i.e., L-3,4- dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP), racetams such
as such as piracetam, oxiracetam, and aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors
such as hordenine and atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea,
Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvulus pluricaulis,
Centella asiatica, Evolvulus alsinoides, Bacopa monnieri, Epimedium herbs,
Ashwagandha herbs, cyclic adenosine monophosphate (cAMP) modulators such as
forskolin, stimulants such as nicotine, caffeine, and amphetamines, cholinergic
compounds and/or acetylcholine modulators such as huperzine-A, dimethylaminoethanol, choline, and alpha-glycerophosphocholine, and combinations
thereof.
[0085] Combination supplements utilizing a racemic R,S-beta-hydroxybutyrate
component may include other supplements/drugs in addition to or as an alternative to the
fat burner component. For example, a combination supplement may include one or more
compounds intended to aid in one or more of appetite suppression, weight loss, reduced
blood glucose level, improved mental alertness, increased physical energy, improved
cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes,
improvement of neurological disorder, reduction of cancer, reduction of
inflammation, anti-aging, antiglycation, reduction in epileptic seizer, improved mood,
increased strength, increased muscle mass, or improved body composition.
[0086] In some embodiments, the ketogenic compositions can include or be administered
together with other vitamin and/or mineral supplements, such as vitamin D3, and D, and
supplements for glucose control, such as berberine and other glucose lowering
substances. It is postulated that a racemic mixture of R- and S-beta-hydroxybutyrate
mixed salt-acid components can provide a longer lasting glucose lowering effect along
with other substances.
V. Administration
[0087] In some embodiments, the compositions disclosed herein can be used in a method
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for increasing ketone body level, including promoting and/or sustaining ketosis, in a
subject comprising administering to a subject in need thereof a nutritionally or
pharmaceutically effective amount of one or more compositions disclosed herein.
Examples of beneficial effects of increasing ketone body level, including promoting
and/or and/orsustaining sustainingketosis, in ain ketosis, subject include a subject one or one include more or of more appetite of suppression, appetite suppression,
weight loss, fat loss, reduced blood glucose level, improved mental alertness, increased
physical energy, improved cognitive function, reduction in traumatic brain injury,
reduction in effect of diabetes, improvement of neurological disorder, reduction of
cancer, reduction of inflammation, anti-aging, antiglycation, reduction in epileptic seizer,
improved mood, increased strength, increased muscle mass, or improved body composition.
[0088] In some embodiments, administering the racemic mixture of R-beta- hydroxybutyrate mixed salt-acid components and S-beta-hydroxybutyrate mixed salt-
acid components provides one or more of increased endogenous production of R-beta-
hydroxybutyrate and acetoacetate; endogenous conversion of the S-beta-hydroxybutyrate
components into one or both of R-beta-hy droxy butyrate R-beta-hydroxybutyrate and and acetoacetate; acetoacetate; endogenous endogenous
conversion of the S-beta-hydroxybutyrate components into fatty acids and sterols;
prolonged ketosis; metabolism of the S-beta-hydroxybutyrate components independent
of conversion to R-beta-hy droxy butyrate R-beta-hydroxybutyrate and/or and/or acetoacetate; acetoacetate; increased increased fetal fetal
development; increased growth years; reduced endogenous production of acetone during
ketosis; signaling by the S-beta-hydroxybutyrate that modulates metabolism of R-beta-
hydroxybutyrate hydroxybutyrate and and glucose; glucose; antioxidant antioxidant activity; activity; and and production production of of acetyl-CoA. acetyl-CoA.
[0089] Ketogenic compositions described herein may be administered to a subject in
therapeutically effective dosages and/or in frequencies to induce or sustain ketosis. In
some embodiments, a single or unit dose will include a total amount of R-beta-
hydroxybutyrate components and S-beta-hydroxybutyrate components ranging from
about 0.5 gram to about 25 grams, or about 0.75 gram to about 20 grams, or about 1
gram to about 15 grams, or about 1.5 grams to about 12 grams.
[0090] The term "unit dose" refers to a dosage form that is configured to deliver a
specified quantity or dose of composition or component thereof. Example dosage forms
include, but are not limited to, tablets, capsules, powders, food products, food additives,
beverages (such as flavored, vitamin fortified, or non-alcoholic), beverage additives
(such as flavored, vitamin fortified, or non-alcoholic), candies, suckers, pastilles, food
supplements, dietetically acceptable sprays (such as flavored mouth spray), injectables
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(such as an alcohol-free injectable), and suppositories. Such dosage forms may be
configured to provide a full unit dose or fraction thereof (e.g., 1/2, 1/3, or 1/4 of a unit
dose).
[0091] Another dosage form that can be used to provide a unit dose of composition or
component thereof is a unit dose measuring device, such as a cup, scoop, syringe,
dropper, spoon, spatula, or colonic irrigation device, which is configured to hold therein
a measured quantity of composition equaling a full unit dose or fraction thereof (e.g.,
1/2, 1/3, or 1/4 of a unit dose). For example, a bulk container, such as a carton, box, can,
jar, bag, pouch, bottle, jug, or keg, containing several unit doses of composition (e.g., 5-
250 or 10-150 unit doses) can be provided to a user together with a unit dose measuring
device that is configured to provide a unit dose, or fraction thereof, of composition or
component thereof.
[0092] A kit for use in providing a composition as disclosed herein in bulk form, while
providing unit doses of the composition, may comprise a bulk container holding therein a
quantity of composition and a unit dose measuring device configured to provide a unit
dose, or fraction thereof, of composition or component thereof. One or more unit dose
measuring devices may be positioned inside the bulk container at the time of sale,
attached to the outside of the bulk container, prepackaged with the bulk container within
a larger package, or provided by the seller or manufacture for use with one or multiple
bulk containers.
[0093] The kit may include instructions regarding the size of the unit dose, or fraction
thereof, and the manner and frequency of administration. The instructions may be
provided on the bulk container, prepackaged with the bulk container, placed on
packaging material sold with the bulk container, or otherwise provided by the seller or
manufacturer (e.g., on websites, mailers, flyers, product literature, etc.) The instructions
may include a reference on how to use the unit dose measuring device to properly deliver
a unit dose or fraction thereof. The instructions may additionally or alternatively include
a reference to common unit dose measuring devices, such as spoons, spatulas, cups, and
the like, not provided with the bulk container (e.g., in case the provided unit dose
measuring device is lost or misplaced). In such case, a kit may be constructed by the end
user when following instructions provided on or with the bulk container, or otherwise
provided by the seller regarding the product and how to properly deliver a unit dose of
composition, or fraction thereof.
[0094] The ketogenic compositions can include or be administered together with other
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supplements, such as vitamin D3, vitamins, minerals, D, vitamins, minerals, nootropics, nootropics, and and others others known known in in the the
art. Examples of vitamins, minerals and herbal supplements that can be added to the
ketogenic compositions include one or more of vitamin A, vitamin C, vitamin E, niacin,
vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese,
chromium, caffeine, theobromine, theacrine, methylliberine, huperzine A, epicatechins,
and enzymes.
[0095] The subject preferably follows a ketogenic diet that restricts intake of
carbohydrates and protein during the period of administration of the composition. In one
example embodiment, the subject may restrict the dietary intake to a ratio of about 65%
fat, about 25% protein, and about 10% carbohydrates. The resulting therapeutic ketosis
provides a rapid and sustained keto-adaptation as a metabolic therapy for a wide range of
metabolic disorders, and provides nutritional support for therapeutic fasting, weight loss,
and performance enhancement. As such, the composition is typically administered once
per day, twice per day, or three times per day to a subject desiring to promote and/or
sustain a state of ketosis.
[0096] In a preferred embodiment, ketogenic compositions can be administered in one or
more unit doses per day via oral administration in solid and/or powdered form, such as in
a powdered mixture (e.g., powder filled gelatin capsules), hard-pressed tablets, or other
oral administration route known to those skilled in the art.
[0097] Although oral administration is preferred, other administration routes may
additionally or alternatively be utilized. For example, some embodiments may be
administered as injectables (e.g., subdermal, parenteral, or intravenous). An injectable
may include one or more of mannitol, 1,3-butanediol, propylene glycol, water, Ringer's
solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and
suspending agents, including synthetic mono- or diglycerides, and fatty acids, including
oleic acid or Cremaphor.
[0098] Exemplary compositions for rectal administration include suppositories which
can contain, for example, a suitable non-irritating excipient, such as cocoa butter,
synthetic glyceride esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquify, soften, and/or dissolve in the rectal cavity at body temperature
to release the supplement.
[0099] Exemplary compositions for nasal or pulmonary administration (e.g., aerosol or
inhalation provided through heating or via nebulization) include solutions in saline which
can contain, for example, benzyl alcohol or other suitable preservatives, absorption
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promoters to enhance bioavailability, and/or other solubilizing or dispersing agents
known in the art.
[00100] 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 any of a variety of factors, such as timing of treatment from previous treatments,
objectives of the treatment, and the like. The duration of administration of the
composition (e.g., the period of time over which the agent is administered), can vary
depending on any of a variety of factors, including subject response, desired effect of
treatment, etc.
[00101] The amount of the composition to be administered can vary according to factors
such as the degree of susceptibility of the individual, the age, sex, and weight of the
individual, idiosyncratic responses of the individual, and the like. The "therapeutically
effective amount" is that amount necessary to promote a therapeutically effective result
in vivo (i.e., therapeutic ketosis). In accordance with the present disclosure, a suitable
single dose size is a dose that is capable of preventing or alleviating (reducing or
eliminating) a symptom in a patient when administered one or more times over a suitable
time period.
[00102] The amount of composition administered will depend on potency, absorption,
distribution, metabolism, and excretion rates of unused ketone bodies, electrolytes, the
method of administration, and the particular disorder being treated, as well as other
factors known to those of skill in the art. The dose should be sufficient to affect a
desirable response, such as a therapeutic or prophylactic response against a particular
disorder or condition, taking into account the severity of the condition to be alleviated.
The compounds may be administered once, or may be divided and administered over
intervals of time. It is to be understood that administration may be adjusted according to
individual need and professional judgment of a person administrating or supervising the
administration of the compositions.
VI. Examples
[00103] The following is a description of exemplary racemic mixtures of R-beta-
hydroxybutyrate and S-beta-hydroxybutyrate and other ketogenic compositions useful
for raising ketone levels in a subject, including inducing and sustaining a ketogenic state
in a subject to which 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. The important thing from
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WO wo 2020/167690 PCT/US2020/017552 PCT/US2020/017552
the standpoint of the examples is the enantiomeric percentages or ratios of R-beta-
hydroxybutyrate and S-beta-hydroxybutyrate. The compositions can include a blend of
R,S--beta-hydroxybutyrate salts and the free R,S-beta-hydroxybutyric acid, to provide a
desired electrolyte balance, taste and/or pharmacokinetic response. In some cases, the
compositions can be a blend of salts, acid, and esters to provide a desired electrolyte
balance and/or modulation of ketosis. The compositions can also be combined with
short, medium, or long chain fatty acids, esters, glycerides, and other supplements as
disclosed herein to provide a desired level of elevated ketone bodies and other effects.
Example 1
[00104] A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition is prepared
by combining one or more R-beta-hydroxybutyrate salt compounds, one or more S-beta-
hydroxybutyrate salt compounds, R-beta-hydroxybutyric acid, and S-beta-
hydroxybutyric acid to provide 50% by enantiomeric equivalents of R-beta-
hydroxybutyrate mixed salt-acid components and 50% by enantiomeric equivalents of S-
beta-hydroxybutyrate mixed salt-acid components. The racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition contains less than 100% by molar
equivalents of racemic R,S-beta-hydroxybutyrate salts and greater than 0% by molar
equivalents of free racemic R,S-beta-hydroxybutyric acids.
Becausethe
[00105] Because theracemic racemic mixture mixtureincludes includes50%50% by enantiomeric equivalents by enantiomeric of R- of R- equivalents
beta-hydroxybutyrate mixed salt-acid compounds, the onset of ketosis is accelerated for
a given dosage as compared to the same dosage enriched with S-beta-hydroxybutyrate
compounds. On the other hand, because the racemic mixture includes 50% by
enantiomeric equivalents of S-beta-hydroxybutyrate mixed salt-acid compounds, the
duration of sustained ketosis is increased for a given dosage as compared to the same
dosage enriched with R-beta-hydroxybutyrate compounds.
[00106] The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition is readily
administered as a ketogenic composition, such as in powder form as a dietary
supplement mixed with food or drink, in the form of one or more capsules or tablets, or
in liquid form such as a mouth spray.
Example 22 Example
[00107] The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of
Example 1 is formulated to provide up to 99.9%, 99.8%, 99.7%, 99.6%, 99.5%, 99.4%,
99.3%, 99.2%, 99.1%, 99%, 98.8%, 98.65%, 98.5%, 98.35%, 98.2%, 98%, 97.75%,
97.5%, 97.25%, or 97%, and at least 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, or
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WO wo 2020/167690 PCT/US2020/017552 PCT/US2020/017552
97%, by molar equivalents of racemic R,S-beta-hydroxybutyrate salts and at least 0.1%,
0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.35%, 1.5%, 1.65%,
1.8%, 2%, 2.25%, 2.5%, 2.75%, or 3%, and less than 25%, 20%, 15%, 10%, 8%, 6%,
5%, 4%, or 3%, by molar equivalents of free racemic R,S-beta-hydroxybutyric acids.
[00108] The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition is readily
administered as a ketogenic composition, such as in powder form as a dietary
supplement mixed with food or drink, in the form of one or more capsules or tablets, or
in liquid form such as a mouth spray.
Example 3
[00109] Example 1 or Example 2 is modified by combining the racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with a dietetically (i.e., nutritionally) or
pharmaceutically acceptable carrier.
Example 4
[00110]
[00110]Any Anyofof thethe foregoing examples foregoing is modified examples by combining is modified the racemic by combining theR,S-beta- racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with one or more short chain fatty acids,
and/or one or more mono-, di- or triglycerides thereof, such as tributyrin.
Example Example 55
[00111]
[00111]Any Anyofof thethe foregoing examples foregoing is modified examples by combining is modified the racemic by combining theR,S-beta- racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with one or more medium chain fatty
acids, and/or one or more mono-, di- or triglycerides thereof, such as MCT oil.
Example 66 Example
[00112]
[00112]Any Anyofof the foregoing the examples foregoing is modified examples by combining is modified the racemic by combining theR,S-beta- racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with one or more long chain fatty acids,
and/or one or more mono-, di- or triglycerides thereof.
Example 77 Example
[00113]
[00113]Any Anyofof thethe foregoing examples foregoing is modified examples by combining is modified the racemic by combining theR,S-beta- racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with one or more supplements, such as
vitamin D3, vitamins, minerals, D, vitamins, minerals, and and others others known known in in the the art. art.
Example Example 88
[00114]
[00114]Any Anyofof thethe foregoing examples foregoing is modified examples by combining is modified the racemic by combining theR,S-beta- racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with one or more fat burner supplements
such as green tea, green tea extract (e.g., a composition including one or more isolated
green tea catechins such as epigallocatechin gallate (EGCG)), green coffee extract,
conjugated linoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleus forskohlii (i.e.,
- Page 28 - forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4-(4- hydroxyphenyl) butan-2-one, p-hydroxybenzyl acetone), ephedrine, synephrine (e.g., bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulators and/or adenosine receptor antagonists (e.g., caffeine), nicotine, coca leaf derivative, ursolic acid, clenbuterol, noradrenaline reuptake inhibitors (e.g., hordenine, atomoxetine), 7-oxodehydroepiandrosterone (i.e., 7-keto DHEA), thyroid hormones (e.g., triiodothyronine), and combinations thereof.
[00115] The resulting combined supplement is expected to provide greater lipolysis
and/or fat oxidation effects than a similar dose utilizing a beta-hydroxybutyrate
component enriched in R-beta-hydroxybutyrate or enriched in S-beta-hydroxybutyrate.
Example 9
[00116] Any of the foregoing examples is modified by combining the racemic R,S-beta-
hydroxybutyrate mixed salt-acid composition with one or more nootropic supplements
such as tyrosine, L-DOPA (i.e., L-3,4-dihydroxyphenylalanine), L-3,4-dihydroxyphenylalanine). tryptophan, and 5-
hydroxytryptophan (5-HTP), racetams such as such as piracetam, oxiracetam, and
aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine,
norepinephrine reuptake inhibitors such as hordenine and atomoxetine, Panax ginseng,
Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia
californica, Convolvulus pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa
monnieri, Epimedium herbs, Ashwagandha herbs, cyclic adenosine monophosphate
(cAMP) modulators such as forskolin, stimulants such as nicotine, caffeine, and
amphetamines, cholinergic compounds and/or acetylcholine modulators such as
huperzine-A, dimethylaminoethanol, choline, and alpha-glycerophosphocholine, and
combinations thereof.
[00117] The resulting combined supplement is expected to provide greater cognition,
alertness, and/or mood effects than a similar dose utilizing a beta-hydroxybutyrate
component enriched in R-beta-hydroxybutyrate or enriched in S-beta-hydroxybutyrate.
The present invention may be embodied in other specific forms without departing from
its spirit or essential characteristics. The described embodiments are to be considered in
all respects only as illustrative and not restrictive. The scope of the invention is,
therefore, indicated by the appended claims rather than by the foregoing description. All
changes which come within the meaning and range of equivalency of the claims are to be
embraced within their scope.
- Page 29 -
Throughoutthis thisspecification specification and and the the claims claims which whichfollow, follow,unless unlessthe the context context requires requires otherwise, otherwise, 16 Apr 2025 2020221569 16 Apr 2025
Throughout
the word the "comprise",and word "comprise", andvariations variationssuch suchasas"comprises" "comprises"and and"comprising", "comprising", willbebeunderstood will understood to to imply theinclusion imply the inclusion of of a stated a stated integer integer or step or step or group or group of integers of integers or but or steps steps notbut thenot the exclusion exclusion of of any otherinteger any other integerororstep step or or group group of integers of integers or steps. or steps.
5 5
The reference in this specification to any prior publication (or information derived from it), or to The reference in this specification to any prior publication (or information derived from it), or to
any matter which whichisis known, known,isis not, not, and and should not be be taken taken as as an an acknowledgment acknowledgment oror admission or or 2020221569
any matter should not admission
any formofofsuggestion any form suggestion thatthat thatthat prior prior publication publication (or information (or information derived derived from it) from it) or or known known matter matter
forms part of forms part of the the common generalknowledge common general knowledge in the in the fieldofofendeavour field endeavourto to which which thisspecification this specification 10 relates. 10 relates.
-Page 30- -Page 30-
Theclaims claimsdefining definingthe theinvention invention areare as as follows: 19 May 2025 2020221569 19 May 2025
The follows:
1. 1. A racemic A racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition for increasing for increasing ketoneketone
level in aa subject, level in subject, comprising: comprising: aa racemic racemic mixture mixture ofofbeta-hydroxybutyric beta-hydroxybutyric acids acids containing containing 50% 50%by by enantiomeric enantiomeric
equivalents of R-beta-hydroxybutyric equivalents of R-beta-hydroxybutyric acid acid and and 50% 50% by by enantiomeric enantiomeric equivalents equivalents of S-beta- of S-beta-
hydroxybutyricacid; hydroxybutyric acid;and and 2020221569
aa racemic racemic mixture mixture ofofbeta-hydroxybutyrate beta-hydroxybutyrate salts salts containing containing 50% 50%bybyenantiomeric enantiomeric equivalents equivalents of of one one or or more R-beta-hydroxybutyrate more R-beta-hydroxybutyrate saltsand salts and50% 50%by by enantiomeric enantiomeric equivalents equivalents of of
one or more one or moreS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts, salts, wherein wherein the the beta-hydroxybutyrate beta-hydroxybutyrate saltssalts are selected are selected
from: from:
sodium R-beta-hydroxybutyrate; sodium R-beta-hydroxybutyrate;
potassiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate;
magnesium magnesium R-beta-hydroxybutyrate; R-beta-hydroxybutyrate;
sodium S-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate;
potassiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calcium S-beta-hydroxybutyrate;and calcium S-beta-hydroxybutyrate; and magnesium magnesium S-beta-hydroxybutyrate; S-beta-hydroxybutyrate;
whereinthe wherein thecomposition composition comprises comprises 75% 75% to 99.9% to 99.9% by equivalents by molar molar equivalents of the racemic of the racemic
mixture ofofbeta-hydroxybutyrate mixture beta-hydroxybutyrate saltsandand salts 25%25% to 0.1% to 0.1% by equivalents by molar molar equivalents of the of the racemic racemic mixture of mixture of beta-hydroxybutyric beta-hydroxybutyricacids, acids, whereinthe wherein the composition compositionisisin in solid solid and/or and/or powder form. powder form.
2. 2. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of claim of claim 1, wherein 1, wherein
the composition the comprisesatatleast composition comprises least two two of: of: aa racemic mixtureof racemic mixture of sodium sodiumR,S-beta-hydroxybutyrate; R,S-beta-hydroxybutyrate; aa racemic mixtureof racemic mixture of potassium potassiumR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate; aa racemic mixtureof racemic mixture of calcium calciumR,S-beta-hydroxybutyrate; R,S-beta-hydroxybutyrate;or or
aa racemic mixtureof racemic mixture of magnesium magnesium R,S-beta-hydroxybutyrate. R,S-beta-hydroxybutyrate
-- Page 31 -- Page 31
2020221569 19 May 2025
3. 3. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixedmixed salt-acid salt-acid composition composition of claimof1 claim or 2, 1 or 2, whereinthe wherein the composition compositioncomprises comprises 80% 80% to 99.7% to 99.7% by molar by molar equivalents equivalents of the of the racemic racemic mixture mixture of of beta-hydroxybutyratesalts beta-hydroxybutyrate salts and and 20% 20%toto0.3% 0.3%byby molar molar equivalents equivalents of of thethe racemic racemic mixture mixture of of beta- beta-
hydroxybutyricacids. hydroxybutyric acids.
4. 4. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of one of any any of oneclaims of claims 2020221569
1-3, 1-3, wherein thecomposition wherein the composition comprises comprises 85% 85% to 99.5% to 99.5% byequivalents by molar molar equivalents of the racemic of the racemic
mixture ofofbeta-hydroxybutyrate mixture beta-hydroxybutyrate saltsandand salts 15%15% to 0.5% to 0.5% by equivalents by molar molar equivalents of the of the racemic racemic mixture of mixture of beta-hydroxybutyric beta-hydroxybutyricacids. acids.
5. 5. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of one of any any of oneclaims of claims 1-4, 1-4, wherein wherein the the composition comprises90% composition comprises 90%to to 99% 99% by molar by molar equivalents equivalents of the of the racemic racemic mixture mixture
of of beta-hydroxybutyrate salts and beta-hydroxybutyrate salts and 10% to1% 10% to 1%bybymolar molar equivalentsofofthe equivalents theracemic racemicmixture mixtureofof beta- beta-
hydroxybutyricacids. hydroxybutyric acids.
6. 6. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of one of any any of oneclaims of claims 1-5, further comprising 1-5, further comprising at least at least oneone short short chainchain fatty fatty acid having acid having less less than than 6 carbons, 6 carbons, or a mono-, or a mono-,
di- di- or or triglyceride ofthe triglyceride of theatatleast leastone oneshort shortchain chain fatty fatty acid. acid.
7. 7. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of one of any any of oneclaims of claims 1-6, 1-6, further furthercomprising comprising at at least leastone onemedium chain fatty medium chain fatty acid acid having having from from 66 to to 12 12 carbons, carbons, such as such as
from from 8 8toto1010 carbons, carbons, or aormono-, a mono-, di- ordi- or triglyceride triglyceride of theof at the at one least leastmedium one medium chain chain fatty acid.fatty acid.
8. 8. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of one of any any of oneclaims of claims 1-7, further comprising 1-7, further at least comprising at least one one fat fatburner burnersupplements selected from supplements selected the group from the consisting of group consisting of green tea,green green tea, greenteatea extract, extract, isolated isolated green green tea catechins, tea catechins, epigallocatechin epigallocatechin gallategreen gallate (EGCG), (EGCG), green coffee extract,conjugated coffee extract, conjugated linoleic linoleic acid acid (CLA), (CLA), tetradecyl tetradecyl thioacetic thioacetic acid Coleus acid (TTA), (TTA), Coleus forskohlii, forskohlii,
yohimbine,rauwolscine, yohimbine, rauwolscine, capsaicin, capsaicin, raspberry raspberry ketones, ketones, 4-(4-hydroxyphenyl) 4-(4-hydroxyphenyl) butan-2-one, butan-2-one, p- p- hydroxybenzylacetone, hydroxybenzyl acetone,ephedrine, ephedrine,synephrine, synephrine,octopamine, octopamine, 1,3-dimethylamylamine, 1,3-dimethylamylamine, higenamine, higenamine,
fucoxanthin, acetylcholine fucoxanthin, acetylcholine modulators, modulators,adenosine adenosine receptor receptor antagonists, antagonists, caffeine, caffeine, nicotine,coca nicotine, coca
-- Page 32 -- Page 32 leaf derivatives, ursolic ursolicacid, acid,clenbuterol, clenbuterol, noradrenaline reuptake inhibitors, hordenine, 19 May 2025 2020221569 19 May 2025 leaf derivatives, noradrenaline reuptake inhibitors, hordenine, atomoxetine,7-oxodehydroepiandrosterone atomoxetine, 7-oxodehydroepiandrosterone, triiodothyronine, triiodothyronine, and and combinations combinations thereof. thereof.
9. 9. The racemic The racemicR,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed mixed salt-acid salt-acid composition composition of one of any any of oneclaims of claims 1-8, 1-8, further furthercomprising comprising at at lease leaseonenootropic onenootropic supplement is selected supplement is selected from the group from the consisting of group consisting of tyrosine, L-DOPA, tyrosine, tryptophan,5-hydroxytryptophan, L-DOPA, tryptophan, 5-hydroxytryptophan, racetams, racetams, piracetam, piracetam, oxiracetam, oxiracetam,
aniracetam, L-theanine, D-serine, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, phosphatidylserine, tolcapone, uridine, uridine, vinpocetine, vinpocetine, 2020221569
norepinephrinereuptake norepinephrine reuptakeinhibitors, inhibitors,hordenine, hordenine, atomoxetine, atomoxetine, PanaxPanax ginseng, ginseng, Ginkgo Ginkgo biloba, biloba, Rhodiolarosea, Rhodiola rosea,Polygala Polygala tenuifolia, tenuifolia, Muira Muira puama,puama, Eschscholzia Eschscholzia californica, californica, Convolvulus Convolvulus
pluricaulis, Centella pluricaulis, Centellaasiatica, asiatica,Evolvulus Evolvulus alsinoides, alsinoides, Bacopa Bacopa monnieri, monnieri, Epimedium Epimedium herbs, herbs, Ashwagandha Ashwagandha herbs, herbs, cyclic cyclic adenosine adenosine monophosphate monophosphate (cAMP) (cAMP) modulators, modulators, forskolin,forskolin, nicotine,nicotine,
caffeine, caffeine, amphetamines, cocaleaf amphetamines, coca leafderivatives, derivatives, cholinergic cholinergic compounds, acetylcholinemodulators, compounds, acetylcholine modulators, huperzine-A,dimethylaminoethanol, huperzine-A, dimethylaminoethanol, choline, choline, alpha-glycerophosphocholine, alpha-glycerophosphocholine, and combinations and combinations
thereof. thereof.
10. 10. The The racemic racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed salt-acid mixed salt-acid composition composition of any of any one one of of claims claims 1-10, 1-10, further furthercomprising comprising a a racemic racemic mixture of one mixture of or more one or R-beta-hydroxybutyrate more R-beta-hydroxybutyrate estersand esters andone one or or more S-beta-hydroxybutyrateesters. more S-beta-hydroxybutyrate esters.
11. 11. A racemic A racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed salt-acid mixed salt-acid composition composition for increasing for increasing ketone ketone level in aa subject, level in subject,comprising: comprising: aa racemic racemic mixture mixture ofofbeta-hydroxybutyric beta-hydroxybutyric acids acids containing containing 50% 50%by by enantiomeric enantiomeric
equivalents of R-beta-hydroxybutyric equivalents of R-beta-hydroxybutyric acid acid and and 50% 50% by by enantiomeric enantiomeric equivalents equivalents of S-beta- of S-beta-
hydroxybutyricacid; hydroxybutyric acid;and and aa racemic racemic mixture mixture ofofbeta-hydroxybutyrate beta-hydroxybutyrate salts salts containing containing 50% 50%bybyenantiomeric enantiomeric equivalents equivalents of of one one or or more R-beta-hydroxybutyrate more R-beta-hydroxybutyrate saltsand salts and50% 50%by by enantiomeric enantiomeric equivalents equivalents of of
one or more one or moreS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts, salts, wherein wherein the the beta-hydroxybutyrate beta-hydroxybutyrate saltssalts are selected are selected
from: from:
sodium R-beta-hydroxybutyrate; sodium R-beta-hydroxybutyrate;
potassiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate;
-- Page 33 -- Page 33 magnesium R-beta-hydroxybutyrate; 19 May 2025 2020221569 19 May 2025 magnesium R-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate; potassiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; calcium S-beta-hydroxybutyrate;and calcium S-beta-hydroxybutyrate; and magnesium magnesium S-beta-hydroxybutyrate; S-beta-hydroxybutyrate; whereinthe wherein thecomposition composition comprises comprises 75% 75% to 99.9% to 99.9% by equivalents by molar molar equivalents of the racemic of the racemic mixture ofofbeta-hydroxybutyrate mixture beta-hydroxybutyrate saltsandand salts 25%25% to 0.1% to 0.1% by equivalents by molar molar equivalents of the of the racemic racemic 2020221569 mixture of mixture of beta-hydroxybutyric beta-hydroxybutyricacids, acids, wherein the composition is provided as or in a tablet, capsule, powder, food product, food wherein the composition is provided as or in a tablet, capsule, powder, food product, food additive, flavoredbeverage, additive, flavored beverage, vitamin vitamin fortified fortified beverage, beverage, non-alcoholic non-alcoholic beverage,beverage, flavored beverage flavored beverage additive, additive, vitamin fortified beverage vitamin fortified additive, non-alcoholic beverage additive, non-alcoholicbeverage beverage additive, additive, candy, candy, sucker, sucker, pastille, food supplement, flavored mouth spray, or suppository. pastille, food supplement, flavored mouth spray, or suppository.
12. 12. The The racemic racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed salt-acid mixed salt-acid composition composition of claimof12, claim 12, wherein wherein
the composition the comprises80%80% composition comprises to 99.7% to 99.7% by molar by molar equivalents equivalents of theofracemic the racemic mixture mixture of of beta- beta- hydroxybutyratesalts hydroxybutyrate saltsand and20% 20% to 0.3% to 0.3% by molar by molar equivalents equivalents of theof the racemic racemic mixturemixture of beta-of beta- hydroxybutyricacids. hydroxybutyric acids.
13. 13. A racemic A racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed salt-acid mixed salt-acid composition composition for increasing for increasing ketone ketone level in aa subject, level in subject,comprising: comprising: aa dietetically or pharmaceutically dietetically or pharmaceutically acceptable acceptable carrier carrier selected selected from from the groupthe group consisting consisting of of tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified beverage, tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified beverage,
non-alcoholic beverage, non-alcoholic beverage,flavored flavoredbeverage beverage additive, additive, vitamin vitamin fortified fortified beverage beverage additive, additive, non-non-
alcoholic alcoholic beverage additive, candy, beverage additive, candy, sucker, sucker, pastille, pastille, food foodsupplement, supplement, flavored mouthspray, flavored mouth spray,and and suppository; suppository;
aa racemic racemic mixture mixture ofofbeta-hydroxybutyric beta-hydroxybutyric acids acids containing containing 50% 50%by by enantiomeric enantiomeric
equivalents of R-beta-hydroxybutyric equivalents of R-beta-hydroxybutyric acid acid and and 50% 50% by by enantiomeric enantiomeric equivalents equivalents of S-beta- of S-beta-
hydroxybutyricacid; hydroxybutyric acid;and and aa racemic racemic mixture mixture ofofbeta-hydroxybutyrate beta-hydroxybutyrate salts salts containing containing 50% 50%bybyenantiomeric enantiomeric equivalents equivalents of of one one or or more R-beta-hydroxybutyrate more R-beta-hydroxybutyrate saltsand salts and50% 50%by by enantiomeric enantiomeric equivalents equivalents of of
one or more one or moreS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts, salts, wherein wherein the the beta-hydroxybutyrate beta-hydroxybutyrate saltssalts are selected are selected
-- Page 34 -- Page 34 from: 19 May 2025 2020221569 19 May 2025 from: sodium R-beta-hydroxybutyrate; sodium R-beta-hydroxybutyrate; potassiumR-beta-hydroxybutyrate; potassium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; calcium R-beta-hydroxybutyrate; magnesium magnesium R-beta-hydroxybutyrate; R-beta-hydroxybutyrate; sodiumS-beta-hydroxybutyrate; sodium S-beta-hydroxybutyrate; potassiumS-beta-hydroxybutyrate; potassium S-beta-hydroxybutyrate; 2020221569 calcium S-beta-hydroxybutyrate;and calcium S-beta-hydroxybutyrate; and magnesium magnesium S-beta-hydroxybutyrate, S-beta-hydroxybutyrate, whereinthe wherein thecomposition composition comprises comprises 75% 75% to 99.9% to 99.9% by equivalents by molar molar equivalents of the racemic of the racemic mixture ofofbeta-hydroxybutyrate mixture beta-hydroxybutyrate saltsandand salts 25%25% to 0.1% to 0.1% by equivalents by molar molar equivalents of the of the racemic racemic mixture of mixture of beta-hydroxybutyric beta-hydroxybutyricacids. acids.
14. 14. The The racemic racemic R,S-beta-hydroxybutyrate R,S-beta-hydroxybutyrate mixed salt-acid mixed salt-acid composition composition of claimof14, claim 14, wherein wherein
the composition the comprises80%80% composition comprises to 99.7% to 99.7% by molar by molar equivalents equivalents of theofracemic the racemic mixture mixture of of beta- beta- hydroxybutyratesalts hydroxybutyrate saltsand and20% 20% to 0.3% to 0.3% by molar by molar equivalents equivalents of theof the racemic racemic mixturemixture of beta-of beta- hydroxybutyricacids. hydroxybutyric acids.
15. 15. A kit A kit forfor administering administering ketone ketone bodies bodies tosubject, to a a subject,comprising: comprising: the racemic the R,S-beta-hydroxybutyratemixed racemic R,S-beta-hydroxybutyrate mixed salt-acidcomposition salt-acid compositionof of any any one one of of claims claims 1-1-
16; 16;
aa container container in in which which the the composition is placed; composition is placed; and and
aa measuring measuringdevice deviceconfigured configured to hold to hold therein therein a unit a unit dose, dose, or fraction or fraction thereof, thereof, of the of the
composition,wherein composition, whereinthe theunit unitdose doseofofthe the composition compositioncontains containsabout about0.5 0.5g gtotoabout about2525g gofofR,S- R,S- beta-hydroxybutyratemixed beta-hydroxybutyrate mixed salt-acidcompounds. salt-acid compounds.
16. 16. The The kit kit of claim of claim 16,16, wherein wherein the the container container is selected is selected from from thethe group group consisting consisting of of carton, carton,
box, can, jar, bag, pouch, bottle, jug, and keg. box, can, jar, bag, pouch, bottle, jug, and keg.
17. 17. TheThe kitkit of of claim1616 claim or or 17,wherein 17, whereinthethemeasuring measuringdevice deviceisisselected selected from from the the group group consisting consisting ofofcup, cup,scoop, scoop, syringe, syringe, dropper, dropper, spatula, spatula, spoon,spoon, and colonic and colonic irrigation irrigation device. device.
- Page - 35 -- Page 35
2020221569 19 May 2025
18. 18. A method A method for increasing for increasing ketoneketone bodyinlevel body level in a subject, a subject, comprising comprising administering administering to a to a subject inneed subject in needthereof thereof a nutritionally a nutritionally or pharmaceutically or pharmaceutically effective effective amount amount of of the composition the composition of of any one of any one of claims claims 11 to to 16, 16, wherein wherein
increasing ketone increasing ketone body body levellevel in subject in the the subject results results in onein orone moreor ofmore of appetite appetite suppression, suppression,
weightloss, weight loss, fat fat loss, loss,reduced reduced blood blood glucose level, improved glucose level, mentalalertness, improved mental alertness,anxiolytic anxiolyticeffects effects (anti-anxiety), (anti-anxiety), faster fasterreaction reaction time, time, increased physicalenergy, increased physical energy,improved improved cognitive cognitive function, function, 2020221569
reduction in reduction in traumatic traumatic brain brain injury, injury, reduction reduction in in effect effect of of diabetes, diabetes, improvement improvementof of neurologicaldisorder, neurological disorder,reduction reduction of cancer, of cancer, reduction reduction of inflammation, of inflammation, anti-aging, anti-aging, anti- anti- glycation, glycation, reduction in epileptic reduction in epileptic seizure, seizure, improved mood,increased improved mood, increased strength,increased strength, increased muscle muscle
mass, or mass, or improved improvedbody body composition; composition; and and S-beta-hydroxybutyrate components S-beta-hydroxybutyrate components in the in the composition composition cause cause at least at least oneone of:of:
increased endogenousproduction increased endogenous production of of R-beta-hydroxybutyrate R-beta-hydroxybutyrate and and acetoacetate; acetoacetate;
endogenousconversion endogenous conversion of of theS-beta-hydroxybutyrate the S-beta-hydroxybutyrate components components into into one one or or both of both of R-beta-hydroxybutyrate andacetoacetate; R-beta-hydroxybutyrate and acetoacetate; endogenous conversion endogenous conversion of of theS-beta-hydroxybutyrate the S-beta-hydroxybutyrate components components into into fatty fatty acids acids
and sterols; and sterols;
prolongedketosis; prolonged ketosis; metabolismofofthe metabolism theS-beta-hydroxybutyrate S-beta-hydroxybutyrate components components independent independent of conversion of conversion
to R-beta-hydroxybutyrate to and/oracetoacetate; R-beta-hydroxybutyrate and/or acetoacetate; increased fetal development; increased fetal development;
increased growthyears; increased growth years; reduced endogenous reduced endogenous production production of of acetone acetone during during ketosis; ketosis;
signaling signaling by by the the S-beta-hydroxybutyrate components S-beta-hydroxybutyrate components that that modulates modulates metabolism metabolism
of of R-beta-hydroxybutyrate andglucose; R-beta-hydroxybutyrate and glucose; antioxidant activity; or antioxidant activity; or
production of production of acetyl-CoA. acetyl-CoA.
- Page - 36 -- Page 36
(grams) dose BHB (grams) dose BHB 30
ester ester
salt salt
free free acid acid 20
10
0 1 1 2 3 4 5 6 7
FIG. 1A
100 Scale) (Relative Side-Effects of Occurrence/Intensity Scale) (Relative Side-Effects of Occurrence/Intensity 80
60
40
20
0 BHB Administered
100 single form double double stack stack triple triple stack stack
FIG. 1B
SUBSTITUTE SHEET (RULE 26)
Concentration Plasma Body Ketone Concentration Plasma Body Ketone 160
140 units) (arbitrary units) (arbitrary 120
100
80
60
40
20
0 1 2 3 6 7 0 2 4 5 Time (arbitrary units)
Free Acid Salt Ester R Stack R/S Stack
FIG. 2
100
80 Oxidation Fat / Lipolysis Oxidation Fat / Lipolysis Scale) (Relative Scale) (Relative 60
40
20
0 0 0.5 1 1.5 2 2.5 3 3.5 4 4 4.5 5
Hours
R enriched Senriched S enriched Racemic
FIG. 3
SUBSTITUTE SHEET (RULE 26)
Claims
1. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone level in a subject, comprising:
a racemic mixture of beta-hydroxybutyric acids containing 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta- hydroxybutyric acid; and
a racemic mixture of beta-hydroxybutyrate salts containing 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts, wherein the beta-hydroxybutyrate salts are selected from:
sodium R-beta-hydroxybutyrate;
potassium R-beta-hydroxybutyrate;
calcium R-beta-hydroxybutyrate;
magnesium R-beta-hydroxybutyrate;
sodium S-beta-hydroxybutyrate;
potassium S-beta-hydroxybutyrate;
calcium S-beta-hydroxybutyrate; and
magnesium S-beta-hydroxybutyrate;
wherein the composition is in solid and/or powder form.
2. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 1, wherein the composition comprises at least two of:
a racemic mixture of sodium R, S-beta-hydroxybutyrate;
a racemic mixture of potassium R, S-beta-hydroxybutyrate;
a racemic mixture of calcium R, S-beta-hydroxybutyrate; or
a racemic mixture of magnesium R, S-beta-hydroxybutyrate.
3. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 1 or 2, wherein the composition comprises 75% to 99.9% by molar equivalents of the racemic mixture of beta-hydroxybutyrate salts and 25% to 0.1% by molar equivalents of the racemic mixture of beta-hydroxybutyric acids.
4. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-3, wherein the composition comprises 80% to 99.7% by molar equivalents of the racemic mixture of beta-hydroxybutyrate salts and 20% to 0.3% by molar equivalents of the racemic mixture of beta-hydroxybutyric acids.
5. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-4, wherein the composition comprises 85% to 99.5% by molar equivalents of the racemic mixture of beta-hydroxybutyrate salts and 15% to 0.5% by molar equivalents of the racemic mixture of beta-hydroxybutyric acids.
6. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-5, wherein the composition comprises 90% to 99% by molar equivalents of the racemic mixture of beta-hydroxybutyrate salts and 10% to 1% by molar equivalents of the racemic mixture of beta-hydroxybutyric acids.
7. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-6, further comprising at least one short chain fatty acid having less than 6 carbons, or a mono-, di- or triglyceride of the at least one short chain fatty acid.
8. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-7, further comprising at least one medium chain fatty acid having from 6 to 12 carbons, such as from 8 to 10 carbons, or a mono-, di- or triglyceride of the at least one medium chain fatty acid.
9. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-8, further comprising at least one of:
a fat burner supplement for increasing lipolysis and/or fat oxidation; or
a nootropic supplement for increasing cognitive performance, alertness, and/or mood.
10. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 9, wherein the one or more fat burner supplements are selected from the group consisting of green tea, green tea extract, isolated green tea catechins, epigallocatechin gallate (EGCG), green coffee extract, conjugated linoleic acid (CLA), tetradecyl thioacetic acid (TTA), Coleus forskohlii , yohimbine, rauwolscine, capsaicin, raspberry ketones, 4-(4-hydroxyphenyl) butan- 2-one, />-hydroxybenzyl acetone, ephedrine, synephrine, octopamine, 1,3- dimethylamylamine, higenamine, fucoxanthin, acetylcholine modulators and/or adenosine receptor antagonists, caffeine, nicotine, coca leaf derivatives, ursolic acid, clenbuterol, noradrenaline reuptake inhibitors, hordenine, atomoxetine, 7-oxodehydroepiandrosterone, triiodothyronine, and combinations thereof.
11. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of claim 9 or 10, wherein the one or more nootropic compounds are selected from the group consisting of tyrosine, L-DOPA, tryptophan, 5-hydroxytryptophan, racetams, piracetam, oxiracetam, aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine,
norepinephrine reuptake inhibitors, hordenine, atomoxetine, Panax ginseng, Ginkgo biloba, Rhodiola rosea, Polygala tenuifolia, Muira puama, Eschscholzia californica, Convolvulus pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri, Epimedium herbs, Ashwagandha herbs, cyclic adenosine monophosphate (cAMP) modulators, forskolin, nicotine, caffeine, amphetamines, coca leaf derivatives, cholinergic compounds, acetylcholine modulators, huperzine-A, dimethylaminoethanol, choline, alpha- glycerophosphocholine, and combinations thereof.
12. The racemic R,S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-11, further comprising a racemic mixture of one or more R-beta-hydroxybutyrate esters and one or more S-beta-hydroxybutyrate esters.
13. A racemic R, S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone level in a subject, comprising:
a racemic mixture of beta-hydroxybutyric acids containing 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta- hydroxybutyric acid; and
a racemic mixture of beta-hydroxybutyrate salts containing 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts, wherein the beta-hydroxybutyrate salts are selected from:
sodium R-beta-hydroxybutyrate;
potassium R-beta-hydroxybutyrate;
calcium R-beta-hydroxybutyrate;
magnesium R-beta-hydroxybutyrate;
sodium S-beta-hydroxybutyrate;
potassium S-beta-hydroxybutyrate;
calcium S-beta-hydroxybutyrate; and
magnesium S-beta-hydroxybutyrate;
wherein the composition is provided as or in a tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin fortified beverage additive, non-alcoholic beverage additive, candy, sucker, pastille, food supplement, flavored mouth spray, or suppository.
14. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 13, wherein the composition comprises 75% to 99.9% by molar equivalents of the racemic
mixture of beta-hydroxybutyrate salts and 25% to 0.1% by molar equivalents of the racemic mixture of beta-hydroxybutyric acids.
15. A racemic R,S-beta-hydroxybutyrate mixed salt-acid composition for increasing ketone level in a subject, comprising:
a dietetically or pharmaceutically acceptable carrier selected from the group consisting of tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin fortified beverage additive, non-alcoholic beverage additive, candy, sucker, pastille, food supplement, flavored mouth spray, and suppository;
a racemic mixture of beta-hydroxybutyric acids containing 50% by enantiomeric equivalents of R-beta-hydroxybutyric acid and 50% by enantiomeric equivalents of S-beta- hydroxybutyric acid; and
a racemic mixture of beta-hydroxybutyrate salts containing 50% by enantiomeric equivalents of one or more R-beta-hydroxybutyrate salts and 50% by enantiomeric equivalents of one or more S-beta-hydroxybutyrate salts, wherein the beta-hydroxybutyrate salts are selected from:
sodium R-beta-hydroxybutyrate;
potassium R-beta-hydroxybutyrate;
calcium R-beta-hydroxybutyrate;
magnesium R-beta-hydroxybutyrate;
sodium S-beta-hydroxybutyrate;
potassium S-beta-hydroxybutyrate;
calcium S-beta-hydroxybutyrate; and
magnesium S-beta-hydroxybutyrate.
16. The racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of claim 15, wherein the composition comprises 75% to 99.9% by molar equivalents of the racemic mixture of beta-hydroxybutyrate salts and 25% to 0.1% by molar equivalents of the racemic mixture of beta-hydroxybutyric acids.
17. A kit for administering ketone bodies to a subject, comprising:
the racemic R, S-beta-hydroxybutyrate mixed salt-acid composition of any one of claims 1-16;
a container in which the composition is placed; and
a measuring device configured to hold therein a unit dose, or fraction thereof, of the
composition, wherein a unit dose of the composition contains about 0.5 g to about 25 g of R- beta-hydroxybutyrate compounds.
18. The kit of claim 17, wherein the container is selected from the group consisting of carton, box, can, jar, bag, pouch, bottle, jug, and keg.
19. The kit of claim 17 or 18, wherein the measuring device is selected from the group consisting of cup, scoop, syringe, dropper, spatula, spoon, and colonic irrigation device.
20. A method for increasing ketone body level in a subject, comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective amount of the composition of claim 1, wherein
increasing ketone body level in the subject results in one or more of appetite suppression, weight loss, fat loss, reduced blood glucose level, improved mental alertness, anxiolytic effects (anti-anxiety), faster reaction time, increased physical energy, improved cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes, improvement of neurological disorder, reduction of cancer, reduction of inflammation, anti-aging, antiglycation, reduction in epileptic seizer, improved mood, increased strength, increased muscle mass, or improved body composition; and
S-beta-hydroxybutyrate components in the composition cause at least one of:
increased endogenous production of R-beta-hydroxybutyrate and acetoacetate; endogenous conversion of the S-beta-hydroxybutyrate components into one or both of R-beta-hydroxybutyrate and acetoacetate;
endogenous conversion of the S-beta-hydroxybutyrate components into fatty acids and sterols;
prolonged ketosis;
metabolism of the S-beta-hydroxybutyrate components independent of conversion to R-beta-hydroxybutyrate and/or acetoacetate;
increased fetal development;
increased growth years;
reduced endogenous production of acetone during ketosis;
signaling by the S-beta-hydroxybutyrate components that modulates metabolism of R-beta-hydroxybutyrate and glucose;
antioxidant activity; or
production of acetyl-CoA.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16/272,145 | 2019-02-11 | ||
| US16/272,145 US10736861B2 (en) | 2016-03-11 | 2019-02-11 | Mixed salt compositions for producing elevated and sustained ketosis |
| US201962805054P | 2019-02-13 | 2019-02-13 | |
| US62/805,054 | 2019-02-13 | ||
| US16/720,211 | 2019-12-19 | ||
| US16/720,211 US11020362B2 (en) | 2016-03-11 | 2019-12-19 | Beta-hydroxybutyrate mixed salt compositions and methods of use |
| US16/783,956 | 2020-02-06 | ||
| US16/783,956 US10973792B2 (en) | 2019-02-13 | 2020-02-06 | Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
| PCT/US2020/017552 WO2020167690A1 (en) | 2019-02-11 | 2020-02-10 | Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use |
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| US20220249497A1 (en) * | 2021-02-05 | 2022-08-11 | Health Via Modern Nutrition, Inc. | Compositions and methods for improving relaxation, sleep, cognition, and/or physical performance |
| US20240196917A1 (en) * | 2021-06-01 | 2024-06-20 | Osaka Gas Co., Ltd. | Oil and fat composition containing 3-hydroxybutyric acid |
| CN115251375A (en) * | 2022-07-11 | 2022-11-01 | 珠海麦得发生物科技股份有限公司 | A kind of (R)-3-hydroxybutyric acid ketone product and preparation method thereof |
| CN115153005A (en) * | 2022-07-27 | 2022-10-11 | 南京纽邦生物科技有限公司 | Beta-hydroxybutyric acid compositions |
| US12059398B2 (en) | 2022-08-26 | 2024-08-13 | Health Via Modern Nutrition Inc. | Compositions of 1,3-butanediol and beta-hydroxybutyric acid to provide optimal therapeutic ketosis |
| EP4595774A1 (en) * | 2022-09-27 | 2025-08-06 | Nanjing Nutrabuilding Bio-Tech Co., Ltd. | Complex of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate and preparation method therefor |
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| US8124589B2 (en) | 2000-05-01 | 2012-02-28 | Accera, Inc. | Use of ketogenic compounds for treatment of age-associated memory impairment |
| JP2004035417A (en) | 2002-06-28 | 2004-02-05 | Kao Corp | Blood total ketone body concentration enhancer |
| KR102499654B1 (en) * | 2013-03-19 | 2023-02-13 | 유니버시티 오브 사우스 플로리다 | Compositions and methods for producing elevated and sustained ketosis |
| CA3021784A1 (en) * | 2016-04-19 | 2017-10-26 | Keto Patent Group, Inc. | Administration of butyrate, beta-hydroxybutyrate, and related compounds in humans |
| US20180021281A1 (en) | 2016-07-20 | 2018-01-25 | Sciadonics, Inc. | Lipid formulations containing bioactive fatty acids and other bioactive agents |
| US10588877B2 (en) | 2016-07-21 | 2020-03-17 | Savind, Inc. | Compositions comprising β-hydroxybutyric acid and salt, and methods of using the same |
| US20180057846A1 (en) * | 2016-08-30 | 2018-03-01 | KetoneAid Inc. | Partially buffered free acid and/or ketone blend for rapid onset ketosis and metabolic therapy |
| WO2018114309A1 (en) | 2016-12-23 | 2018-06-28 | Katholieke Universiteit Leuven | 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment |
| MX2020000734A (en) * | 2017-07-21 | 2020-07-29 | Buck Inst Res Aging | S-enantiomers of beta-hydroxybutyrate and butanediol and methods for using same. |
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