Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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
to [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 shift to the creation and use of ketone bodies 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.,
13-
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 1-
CA 03129541 2021-08-09
WO 2020/167690
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 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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] Some compositions used to promote ketosis in a mammal 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 5-beta-
hydroxybutyrate, and
racemic mixtures of R-and 5-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 5-beta-hydroxybutyrate (aka (35)-hydroxybutyrate) is ineffective or
even
harmful.
BRIEF SUMMARY
[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 5-beta-hydroxybutyrate
salts. A
"racemic mixture" of R,S-hydroxybutyric acids includes enantiomerically
equivalent
amounts (50:50) of R- and 5-beta-hydroxybutyric acids.
[0012] R-beta-hydroxybutyrate is the endogenous form produced by a mammal, and
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 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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 R-beta-hydroxybutyrate that can be immediately utilized by the 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-hydroxybutyrate mixed salt-acid components in
enantiomerically equivalent ratios can result in at least one of: (1)
increased endogenous
production of R-beta-hydroxybutyrate 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-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 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
- Page 4 -
CA 03129541 2021-08-09
WO 2020/167690
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 mixed 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 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
provided as free acids (i.e., R-beta-hydroxybutyric acid and S-beta-
hydroxybutyric acid),
salts thereof (i.e., R-beta-hydroxybutyrate salt(s) and S-beta-hydroxybutyrate
salt(s)),
and optionally esters thereof (i.e., R-beta-hydroxybutyrate ester(s) and S-
beta-
hydroxybutyrate ester (s)). Providing beta-hydroxybutyrate as a double racemic
stack
that combines at least four separate forms (or triple racemic stack that
combines six
separate forms) of beta-hydroxybutyrate may beneficially allow the use of
higher
amounts of beta-hydroxybutyrate for a given administered dose and/or allow for
more
doses per day. Each form of beta-hydroxybutyrate is typically associated with
its own
particular positive attributes and negative side effects. Stacking different
forms of beta-
hydroxybutyrate allows for delivery of more of the positive attributes
compared to each
being used alone. Similarly, stacking different forms of beta-hydroxybutyrate
reduces or
mitigates the negative side effects of each particular form of beta-
hydroxybutyrate so
that such negative effects can be "spread-out" and limited. In either case,
stacking
increases or maximizes the overall dose of beta-hydroxybutyrate that can be
efficaciously delivered.
[0021] Additional features and advantages will be set forth in part in the
description that
follows, and in part will be obvious from the description, or may be learned
by practice
of the embodiments disclosed herein. It is to be understood that both the
foregoing brief
summary and the following detailed description are exemplary and explanatory
only and
are not restrictive of the embodiments disclosed herein or as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1A illustrates higher levels of the amount of beta-
hydroxybutyrate
administered when using a "stacked" dose of at least two different forms of
racemic R,S-
beta-hydroxybutyrate as compared to single forms of racemic R,S-beta-
hydroxybutyrate;
[0023] Figure 1B illustrates expected relative rates of undesirable side-
effects resulting
from treatment with various formulations of beta-hydroxybutyrate, where a
"double
stack" (i.e., double racemic stack) formulation comprising 1) free R,S-beta-
hydroxybutyric acids and (2) R,S-beta-hydroxybutyrate salts and a "triple
stack" (i.e.,
triple racemic stack) formulation further comprising R,S-beta-hydroxybutyric
esters on
top of the double stack are expected to allow for administration of greater
amounts of
beta-hydroxybutyrate and/or reduced occurrences or intensities of side-effects
as
compared to administering single forms of beta-hydroxybutyrate;
[0024] Figure 2 compares expected release profiles of R,S-beta-hydroxybutyrate
stack
compositions to free acid, salt, and ester single forms and also an R-beta-
- Page 6 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
hydroxybutyrate stack, illustrating that stacked R,S-compositions provide an
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 0-hydroxybutyrate, 3-
hydroxybutyrate, 01-113, or BHB, is the deprotonated form of beta-
hydroxybutyric acid,
which is a hydroxycarboxylic acid having the general formula CH3CH2OHCH2COOH.
The deprotonated form present at typical biological pH levels is
CH3CH2OHCH2C00-.
The general chemical structure shown below represents beta-hydroxybutyrate
compounds that may be utilized in the disclosed compositions:
HO 0
where,
X can be hydrogen, metal ion, amino cation such as from an 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, liquid, solution, suspension, or gel.
[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-
- Page 7 -
CA 03129541 2021-08-09
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 acid in the 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 (H30+) and a beta-hydroxybutyrate anion (e.g., dissolved
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 (H30+). As a
result,
beta-hydroxybutyric acid molecules can exchange protons and cations with
dissolved
- Page 8 -
CA 03129541 2021-08-09
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 salt(s). The total quantity of free beta-hydroxybutyric acid
molecules in
solution is the sum of dissolved beta-hydroxybutyric acid molecules that are
not
deprotonated and beta-hydroxybutyrate anions formed by deprotonation of beta-
hydroxybutyric acid molecules.
[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 the molar
fraction of beta-hydroxybutyrate molecules from the beta-hydroxybutyrate
salt(s)) in
solution is [(ii) (i)]. Multiplying the molar fraction of each by 100 gives
the percentage
of each in solution.
[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 -
CA 03129541 2021-08-09
WO 2020/167690
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] B eta-hy droxybuty rate, typically R-beta-hy droxy butyrate, 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.
[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 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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.
1() 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."
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-hydroxybutyrate esters and 50% by enantiomeric equivalents of
one 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 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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 mixed 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 compounds in both salt and acid 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-hydroxybutyrate enantiomer, the endogenous form produced by a mammal,
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-hydroxybutyrate enantiomer is endogenously
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-hydroxybutyrate enantiomer components,
in
addition to a relatively more extended, sustained increase to blood ketone
body levels
- Page 12 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
primarily by way of the S-beta-hydroxybutyrate enantiomer components. Such
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, 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-hydroxybutyrate
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-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 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 mixed 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
- Page 13 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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)-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, 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
- Page 14 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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] The administration of a racemic mixture 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, thereby exploiting the metabolic and physiological 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
- Page 15 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
therapeutically effective amount of vitamin D3. Vitamin D3 is believed to work
in
conjunction with magnesium and calcium to promote good bone health and to
prevent
undesirable calcification of soft tissues. In preferred embodiments, vitamin
D3 is
included in an amount such that an average daily dose of the ketogenic
composition
includes about 200 IU ("International Units") to about 8000 IU, or about 400
IU to about
4000 IU, or about 600 IU to about 3000 IU of vitamin D3. In some embodiments,
vitamin
D3 is included in an amount such that an average daily dose of the ketogenic
composition
includes about 5 pg to about 200 [tg, or about 10 pg to about 100 [tg, or
about 15 pg to
about 75 lig of vitamin D3.
[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 mixed 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
- Page 16 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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) is therefore utilized to form the mixed salt-acid
compositions.
Because beta-hydroxybutyric acid has a pKa of 4.70, it deprotonates and
produces 1-1+ at
physiological pH. The resulting excess acidity can cause undesirable side
effects
including causing or aggravating gastrointestinal issues such as ulcers or
refli.ix.
[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-
- Page 17 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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
- Page 18 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
about 80%, or about 30% to about 70%, or about 40% to about 60% on a molar
basis of
beta-hy droxy butyrate.
[0074] An example beta-hydroxybutyrate triple stack includes a beta-
hydroxybutyrate
ester 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, 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
- Page 19 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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-
hy droxy butyrate.
[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
- Page 20 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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-hydroxybutyrate, the
level 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-
beta-hydroxybutyrate components and S-beta-hydroxybutyrate components function
to
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-hydroxybutyrate components and 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., hordenine, atomoxetine), 7-
oxodehy droepi andro sterone (i. e. , 7 -keto DHEA),
thyroid 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
- Page 21 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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-
hy droxy butyrate.
[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
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
- Page 22 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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 sustaining ketosis, in a subject include one or more of 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-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 that modulates metabolism of
R-beta-
hydroxybutyrate and glucose; antioxidant activity; and production of 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
- Page 23 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
(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
- Page 24 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
supplements, such as vitamin D3, vitamins, minerals, nootropics, and others
known in 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
- Page 25 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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
- Page 26 -
CA 03129541 2021-08-09
WO 2020/167690
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 5-
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.
[00105] Because the racemic mixture includes 50% by enantiomeric equivalents
of R-
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 2
[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
- Page 27 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
970o, by molar equivalents of racemic R,S-beta-hydroxybutyrate salts and at
least 0.100,
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%,
1.80o, 20o, 2.250o, 2.50o, 2.750o, or 30o, and less than 250o, 200o, 150o,
10%, 80o, 60o,
500, 40o, or 30o, 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] Any of the foregoing examples is modified by combining the 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 5
[00111] Any of the foregoing examples is modified by combining the 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 6
[00112] Any of the foregoing examples is modified by combining the 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 7
[00113] Any of the foregoing examples is modified by combining the racemic R,S-
beta-
hydroxybutyrate mixed salt-acid composition with one or more supplements, such
as
vitamin D3, vitamins, minerals, and others known in the art.
Example 8
[00114] Any of the foregoing examples is modified by combining the 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 -
CA 03129541 2021-08-09
WO 2020/167690
PCT/US2020/017552
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), 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 -
