AU2020222897B2 - Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use - Google Patents

Abstract

Ketogenic compositions include a non-racemic mixture of beta-hydroxybutyrate salts and acid(s) enriched with the R-enantiomer. The compositions are enriched with the R-enantiomer to elevate ketone bodies and increase the rate at which ketosis is achieved yet contains an amount of the S-enantiomer to provide alternative benefits. Beta-hydroxybutyric acid is more rapidly absorbed and utilized by the body than salts or esters, enhances taste, and reduces the need to include citric acid or other edible acids. Beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and can provide one or more electrolytes. Compositions for increasing ketone body level in a subject may contain a dietetically or pharmaceutically acceptable carrier and a non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate, wherein the non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate contains from about 50.5% to 99.5% by enantiomeric equivalents of R-beta-hydroxybutyrate and from about 49.5% to about 0.5% by enantiomeric equivalents of S-beta-hydroxybutyrate.

Description

WO wo 2020/167692 PCT/US2020/017555

NON-RACEMIC BETA-HYDROXYBUTYRATE COMPOUNDS AND COMPOSITIONS ENRICHED WITH THE R-ENANTIOMER AND METHODS OF USE

BACKGROUND 1. Field of The Invention

[0001] Disclosed herein are mixed, non-racemic beta-hydroxybutyrate compounds, salts,

acids, and esters thereof, and compositions enriched with the R-enantiomer of beta-

hydroxybutyrate and use in producing elevated blood levels of ketone bodies in a

subject. 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 shift metabolically 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- "ß-

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,

WO wo 2020/167692 PCT/US2020/017555

including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle

sparing properties, and improved cognitive and physical performance. Science-based

improvements in efficiency of cellular metabolism, managed through ketone supplementation, can beneficially impact physical, cognitive health, and psychological

health, and have 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 entering ketosis through depleting

glucose stores in the body is by 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 ketogenisis, exiting the body from its state of ketosis, as the

body 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 drop in insulin levels caused by

ketosis effects the rate at which certain electrolytes are extracted by the kidneys,

additionally lowering electrolyte levels in the body. Negative effects of electrolyte

imbalance include muscle aches, spasms, twitches and weakness, restlessness, anxiety,

WO wo 2020/167692 PCT/US2020/017555

frequent frequent headaches, headaches, feeling feeling very very thirsty, thirsty, insomnia, insomnia, fever, fever, heart heart palpitations palpitations or or irregular 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 a racemic

mixture of beta-hydroxybutyrate (RS-beta-hydroxybutyrate or DL-beta- hydroxybutyrate). Other compositions, such as those disclosed in U.S. Patent Publication

No. 2017/0296501 to Lowery et al., 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. 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. Other enantiomers,

such as (3R)-hydroxybutyl (3S)-hydroxybutyrate, (3S)-hydroxybutyl (3R)- hydroxybutyrate, and (3S)-hydroxybutyl (3S)-hydroxybutyrate, are mostly or entirely

omitted. The omission of enantiomers that are not the endogenous form of beta-

hydroxybutyrate is based on the view that S-beta-hydroxybutyrate (aka (3S)-

hydroxybutyrate) is ineffective or even harmful.

BRIEF SUMMARY

[0010]

[0010] Disclosed Disclosedherein are are herein ketogenic compositions ketogenic and methods compositions for increasing and methods ketone for increasing ketone

body level in a subject, including promoting and/or sustaining ketosis in a subject.

Example Examplecompositions compositionsinclude a non-racemic include mixturemixture a non-racemic of R-beta-hy droxy butyrate and S- of R-beta-hydroxybutyrate and S-

beta-hydroxybutyrate, wherein the non-racemic mixture is enriched with the R-beta-

hydroxybutyrate enantiomer relative to the S-beta-hydroxybutyrate enantiomer, such as

50.5% 50.5% to to99.5% 99.5%by by enantiomeric equivalents enantiomeric of the of equivalents R-beta-hy droxy butyrate enantiomer the R-beta-hydroxybutyrate enantiomer

and 49.5% to 0.5% by enantiomeric equivalents of the S-beta-hydroxybutyrate

enantiomer. enantiomer.

[0011]

[0011] The Thenon-racemic mixture non-racemic of R-beta-hy mixture droxybutyrate and S-beta-hydroxybutyrate of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate

contains more of the R-beta-hydroxybutyrate enantiomer (i.e., more than 50% and less

than 100%), the endogenous form produced by a mammal, than the S-beta- hydroxybutyrate enantiomer (i.e., less than 50% and more than 0%) in order to provide a

greater and/or faster ketogenic effect compared to a racemic mixture. Because the R-

beta-hydroxybutyrate enantiomer is endogenously produced by a mammal during

ketosis, administering the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer toto a a subject subject provides provides anan additional additional quantity quantity and/or increased blood bloodplasma plasmalevel levelthat thatcan canbebeimmediately immediately utilized by by thethe 20 Jun 2025 2020222897 20 Jun 2025 and/or increased utilized body, such as for producing energy (e.g., as an alternative energy source to glucose). body, such as for producing energy (e.g., as an alternative energy source to glucose).

[0012] Nevertheless,and

[0012] Nevertheless, andcontrary contrary to to conventional conventional wisdom wisdom to minimize to minimize or eliminate or eliminate S-beta- S-beta-

hydroxybutyrate, which hydroxybutyrate, which is is not not endogenously endogenously produced by aa mammal produced by mammal andand is is believedtotobebe believed

5 unnatural 5 unnatural andand potentially potentially harmful, harmful, thethe non-racemic non-racemic mixture mixture contains contains a significant a significant quantity quantity of the of the

S-beta-hydroxybutyrate enantiomer S-beta-hydroxybutyrate enantiomer inin ordertotoproduce order produceone oneorormore moredesired desiredeffects effects in in the the mammal, mammal, 2020222897

as discussedherein. as discussed herein.

[0013] In addition,

[0013] In addition, while conventionalcompositions while conventional compositions typicallycontain typically containpolymer, polymer, oligomer, oligomer, ester, ester,

or salt or salt forms of beta-hydroxybutyrate, forms of beta-hydroxybutyrate, the the non-racemic non-racemic mixtures mixtures enriched enrichedwith withR-beta- R-beta- 10 hydroxybutyrate 10 hydroxybutyrate relative relative to S-beta-hydroxybutyrate to S-beta-hydroxybutyrate can include can include theacid the free freeform acidofform of R-beta- R-beta-

hydroxybutyrateand/or hydroxybutyrate and/orS-beta-hydroxybutyrate. S-beta-hydroxybutyrate. For For example, example, a non-racemic a non-racemic mixture mixture may may contain contain

one or more one or salts or more salts or esters estersofofR-beta-hydroxybutyrate R-beta-hydroxybutyrate and S-beta-hydroxybutyrateinincombination and S-beta-hydroxybutyrate combination with R-beta-hydroxybutyric with R-beta-hydroxybutyric acid,andand acid, optionally optionally S-beta-hydroxybutyric S-beta-hydroxybutyric acid.acid. Combining Combining beta- beta-

hydroxybutyricacid hydroxybutyric acidwith withone oneorormore more beta-hydroxybutyrate beta-hydroxybutyrate salts salts is is beneficialbecause beneficial becauseititreduces reduces 15 electrolyteload, 15 electrolyte load,increases increases absorption absorption rate, rate, improves improves taste, taste, facilitates facilitates easier easier formulation, formulation, and and

reduces the need to add citric acid or other edible acids to obtain a composition having neutral or reduces the need to add citric acid or other edible acids to obtain a composition having neutral or

acidic acidic pH. pH.

[0014] In some

[0014] In someembodiments, embodiments, the the compositions compositions disclosed disclosed hereinherein can becan beinused used in a for a method method for increasing ketone increasing ketonebody bodylevel levelinina asubject, subject,including including promoting promoting and/or and/or sustaining sustaining ketosis ketosis in a in a 20 subject,comprising ?O subject, comprising administering administering to atosubject a subject in in need need thereof thereof a nutritionallyororpharmaceutically a nutritionally pharmaceutically effective amount effective of one amount of one or or more morecompositions compositions disclosedherein. disclosed herein.Examples Examplesof of beneficial beneficial effectsofof effects

increased ketone body level in a subject include one or more of appetite suppression, weight loss, increased ketone body level in a subject include one or more of appetite suppression, weight loss,

fat loss, fat loss, reduced bloodglucose reduced blood glucoselevel, level,improved improved mental mental alertness, alertness, increased increased physical physical energy, energy,

improved cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes, improved cognitive function, reduction in traumatic brain injury, reduction in effect of diabetes,

25 improvement 25 improvement of neurological of neurological disorder, disorder, reduction reduction of cancer, of cancer, reduction reduction of inflammation, of inflammation, anti-aging, anti-aging,

antiglycation, reduction antiglycation, reduction in in epileptic epileptic seizure, seizure, improved improved mood, increased mood, increased strength, strength, increased increased muscle muscle mass, or mass, or improved bodycomposition. improved body composition.

[0015] In some

[0015] In someembodiments, embodiments, administering administering the the non-racemic non-racemic mixture mixture of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate

and S-beta-hydroxybutyrate and S-beta-hydroxybutyrateininenantiomeric enantiomeric ratiosororpercentages ratios percentages disclosed disclosed herein herein provides provides oneone

30 30 or or more more of: of: increased increased endogenous endogenous production production of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate andand acetoacetate; acetoacetate;

endogenousconversion endogenous conversion of of theS-beta-hydroxybutyrate the S-beta-hydroxybutyrate

4 into into one or both both of of R-beta-hydroxybutyrate R-beta-hydroxybutyrate andand acetoacetate; endogenous conversion of theofS-the S- 20 Jun 2025 Jun 2025 one or acetoacetate; endogenous conversion beta-hydroxybutyrateinto beta-hydroxybutyrate intofatty fatty acids acids and andsterols; sterols; prolonged prolongedketosis; ketosis;metabolism metabolismof of thethe S-beta- S-beta- hydroxybutyrateindependent hydroxybutyrate independent of conversion of conversion to R-beta-hydroxybutyrate to R-beta-hydroxybutyrate and/or acetoacetate; and/or acetoacetate; increased fetal development; increased fetal increasedgrowth development; increased growthyears; years;reduced reducedendogenous endogenous production production of acetone of acetone 2020222897 20

5 5 during ketosis; signaling during ketosis; signaling by by the the S-beta-hydroxybutyrate S-beta-hydroxybutyrate thatmodulates that modulates metabolism metabolism of R-beta- of R-beta-

hydroxybutyrateand hydroxybutyrate andglucose; glucose;antioxidant antioxidantactivity; activity; and and production productionofof acetyl-CoA. acetyl-CoA. 2020222897

[0016] Thecomposition

[0016] The composition may may include include a nutritionallyororpharmaceutically a nutritionally pharmaceutically acceptable acceptable carrier. carrier.

[0016A]

[0016A] In In some some embodiments, embodiments, the disclosure the disclosure provides provides a composition a composition for administering for administering ketoneketone

bodies to a subject, comprising: bodies to a subject, comprising:

10 10 aa non-racemic mixtureofofR-beta-hydroxybutyrate non-racemic mixture R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate S-beta-hydroxybutyrate containing containing

50.5% 50.5% toto99.5% 99.5%by by enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and 49.5% and 49.5% to 0.5% to by0.5% by

enantiomericequivalents enantiomeric equivalentsof of S-beta-hydroxybutyrate, S-beta-hydroxybutyrate,wherein wherein thenon-racemic the non-racemic mixture mixture of R-beta- of R-beta-

hydroxybutyrateand hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate includes: includes:

at at least least one R-beta-hydroxybutyrate one R-beta-hydroxybutyrate salt; salt;

15 15 at at least least one S-beta-hydroxybutyrate one S-beta-hydroxybutyrate salt; salt; and and

at at least least one of R-R-ororS-beta-hydroxybutyric one of S-beta-hydroxybutyricacid, acid, and and whereinthe wherein the composition compositionisisaa powder, powder, whereinthe wherein the non-racemic non-racemicmixture mixturecomprises comprises 75%75% to 99% to 99% by molar by molar equivalents equivalents of combined of combined R- R- beta-hydroxybutyrateand beta-hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate saltsand salts and25% 25% to to 1% 1% by molar by molar equivalents equivalents of of R- R- 20 beta-hydroxybutyric ?O beta-hydroxybutyric acidacid and/or and/or S-beta-hydroxybutyric S-beta-hydroxybutyric acid.acid.

[0016B]

[0016B] In In some some embodiments, embodiments, the disclosure the disclosure provides provides a composition a composition for administering for administering ketoneketone

bodies to a subject, comprising: bodies to a subject, comprising:

aa non-racemic mixtureofofR-beta-hydroxybutyrate non-racemic mixture R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate S-beta-hydroxybutyrate containing containing

50.5% 50.5% toto99.5% 99.5%by by enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and 49.5% and 49.5% to 0.5% to by0.5% by

25 enantiomeric 25 enantiomeric equivalents equivalents of S-beta-hydroxybutyrate, of S-beta-hydroxybutyrate, wherein wherein the non-racemic the non-racemic mixture mixture of R-beta- of R-beta-

hydroxybutyrateand hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate includes: includes:

at at least least one R-beta-hydroxybutyrate one R-beta-hydroxybutyrate salt salt or or ester; ester;

at at least least one S-beta-hydroxybutyrate one S-beta-hydroxybutyrate saltester; salt or or ester; and and

at least one of R- or S-beta-hydroxybutyric acid, and at least one of R- or S-beta-hydroxybutyric acid, and

30 30 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

5 additive, additive, vitamin fortified beverage additive, non-alcoholic non-alcoholicbeverage beverage additive, candy, sucker, 20 Jun 2025 2020222897 20 Jun 2025 vitamin fortified beverage additive, additive, candy, sucker, pastille, food supplement, flavored mouth spray, or suppository, pastille, food supplement, flavored mouth spray, or suppository, whereinthe wherein the non-racemic non-racemicmixture mixturecomprises comprises 75% 75% to to 99%99% by molar by molar equivalents equivalents of combined of combined

R-beta-hydroxybutyrateand R-beta-hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts salts andand 25%25% to by to 1% 1%molar by molar equivalents equivalents of of 5 5 R-beta-hydroxybutyricacid R-beta-hydroxybutyric acidand/or and/orS-beta-hydroxybutyric S-beta-hydroxybutyric acid acid

[0016C]

[0016C] In In some some embodiments, embodiments, the disclosure the disclosure provides provides a composition a composition for administering for administering ketoneketone

bodies to a subject, comprising: 2020222897

bodies to a subject, 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,

10 non-alcoholic 10 non-alcoholic beverage, beverage, flavored flavored beverage 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; and and

aa non-racemic mixtureofofR-beta-hydroxybutyrate non-racemic mixture R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate S-beta-hydroxybutyrate containing containing

50.5% 50.5% toto99.5% 99.5%by by enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and 49.5% and 49.5% to 0.5% to by0.5% by

15 enantiomeric 15 enantiomeric equivalents equivalents of S-beta-hydroxybutyrate, of S-beta-hydroxybutyrate, wherein wherein the non-racemic the non-racemic mixture mixture of R-beta- of R-beta-

hydroxybutyrateand hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate includes: includes:

at at least leastone oneR-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate ester; R-beta-hydroxybutyrate ester;

at at least leastone oneS-beta-hydroxybutyrate salt or S-beta-hydroxybutyrate salt orS-beta-hydroxybutyrate ester; and S-beta-hydroxybutyrate ester; and

at at least least one of R-R-ororS-beta-hydroxybutyric one of S-beta-hydroxybutyricacid, acid,

20 whereinthe ?O wherein thenon-racemic non-racemicmixture mixturecomprises comprises 75% 75%toto99% 99%bybymolar molarequivalents equivalents of of combined R- combined R-

beta-hydroxybutyrateand beta-hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate saltsand salts and25% 25% to to 1% 1% by molar by molar equivalents equivalents of of R- R- beta-hydroxybutyricacid beta-hydroxybutyric acidand/or and/orS-beta-hydroxybutyric S-beta-hydroxybutyric acid. acid.

[0016D]

[0016D] In In some some embodiments, embodiments, the disclosure the disclosure provides provides kit for a kita for administering administering ketone ketone bodies bodies to to

aa subject, comprising: subject, comprising:

25 25 aa composition as disclosed composition as disclosed herein; herein; aa container container in in which which the the composition is placed; composition is placed; and and

aa measuring device measuring device configured configured totherein to hold hold therein a unitordose, a unit dose, or fraction fraction thereof, thereof, of the composition, of the composition,

whereinaaunit wherein unit dose doseofofthe thecomposition composition contains contains about about 0.5 0.5 g about g to to about 25 g25 ofgthe of non-racemic the non-racemic mixture of mixture of R-beta-hydroxybutyrate R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

5A 5A

[0016E] In some embodiments, the disclosure provides the usethe of use of a composition as disclosed 20 Jun 2025 20 Jun 2025

[0016E] In some embodiments, the disclosure provides a composition as disclosed

herein in herein in the the manufacture of aa medicament manufacture of forincreasing medicament for increasingblood bloodketone ketonelevel levelinin aa subject, subject, wherein wherein

increasing blood increasing ketonelevel blood ketone level in in the the subject subject causes one or causes one or more moreof: of:appetite appetite suppression, suppression, weight weight loss, loss, fat fat loss, loss, reduced blood reduced blood glucose glucose level, level, improved improved mental mental alertness, alertness, increasedincreased physical energy, physical energy,

5 improved 5 improved cognitive cognitive function, function, reduction reduction in traumatic in traumatic brain brain injury, injury, reduction reduction in effect in effect of of diabetes, diabetes,

improvement improvement ofof neurologicaldisorder, neurological disorder,reduction reductionofofcancer, cancer, reduction reduction of of inflammation, inflammation,anti-aging, anti-aging, 2020222897

2020222897

anti¬glycation, reduction ininepileptic anti-glycation, reduction epileptic seizure, seizure, improved improved mood, mood, increased increased strength, strength, increased increased

musclemass, muscle mass,ororimproved improved body body composition. composition.

[0016F]

[0016F] In In some some embodiments, embodiments, the disclosure the disclosure provides provides a method a method for increasing for increasing blood ketone blood ketone

10 level 10 level in in a subject,comprising a subject, comprising administering administering a composition a composition as disclosed as disclosed hereinherein to the to the subject, subject,

whereinincreasing wherein increasingblood bloodketone ketonelevel levelcauses causesone one or or more more of:of: appetite appetite suppression, suppression, weight weight loss, loss,

fat fat loss, loss, reduced bloodglucose reduced blood glucoselevel, level,improved improved mental mental alertness, alertness, increased increased physical physical energy, energy,

improved cognitive improved cognitive function, function, reduction reduction in traumatic in traumatic brainreduction brain injury, injury, reduction in effect ofindiabetes, effect of diabetes, improvement improvement ofof neurologicaldisorder, neurological disorder,reduction reductionofofcancer, cancer, reduction reduction of of inflammation, anti-aging, inflammation, anti-aging,

15 antiglycation,reduction 15 antiglycation, reductionininepileptic epileptic seizure, seizure, improved mood,increased improved mood, increasedstrength, strength,increased increasedmuscle muscle mass, or mass, or improved bodycomposition. improved body composition.

[0017] Additional

[0017] 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 in part and in partwill willbebeobvious obvious from from the the description, description, orbemay or may be learned learned by practice by practice of the embodiments of the embodiments

disclosed herein. disclosed herein. ItItisistotobebeunderstood understood that thatboth boththe theforegoing foregoingbrief briefsummary andthe summary and thefollowing following 20 detailed ?O detailed descriptionare description areexemplary exemplary and and explanatory explanatory only only andand areare notnot restrictive of restrictive of the the embodiments embodiments

disclosed herein or as claimed. disclosed herein or as claimed.

DETAILED DESCRIPTION DETAILED DESCRIPTION I. I. Introduction Introduction

[0018] The

[0018] compound The compound “beta-hydroxybutyrate,” "beta-hydroxybutyrate," alsoalso knownknown as β-hydroxybutyrate, as -hydroxybutyrate, 3- 3- 25 hydroxybutyrate, 25 hydroxybutyrate, ßHB,βHB, or BHB, or BHB, is theisdeprotonated the deprotonated form form of of beta-hydroxybutyric beta-hydroxybutyric acid, is acid, which which a is a hydroxycarboxylic acid hydroxycarboxylic acid having having the thegeneral generalformula formulaCH 3CH2OHCH2COOH. CHCHOHCHCOOH. The deprotonated The deprotonated − form present form present at at typical typicalbiological pHpHlevels biological is CH levels CH2OHCH2COO is 3CHCHOHCHCOO. . The general The general chemical chemical

structure structure shown belowrepresents shown below representsbeta-hydroxybutyrate beta-hydroxybutyrate compounds compounds thatbemay that may be utilized utilized in the in the

disclosed compositions: disclosed compositions:

5B 5B

2020222897 20 Jun 2025

Ho O X O-X where, where,

X canbebehydrogen, X can hydrogen,metal metal ion,amino ion, amino cation cation such such as from as from an amino an amino acid,acid, alkyl, alkyl, alkenyl, alkenyl,

aryl, aryl, or or acyl. acyl.

5 [0019] WhenWhen X is X is a hydrogen, the compound is beta-hydroxybutyric acid.X When X is ion a metal ion 2020222897

5 [0019] a hydrogen, the compound is beta-hydroxybutyric acid. When is a metal

or or an an amino cation, the amino cation, the compounds compounds isisa abeta-hydroxybutyrate beta-hydroxybutyrate salt.When salt. When X is X is alkyl,alkenyl, alkyl, alkenyl,aryl, aryl, or acyl, or acyl, the thecompounds compounds isis aa beta-hydroxybutyrate beta-hydroxybutyrateester. ester.The Theforegoing foregoingcompounds compounds can can beany be in in any desired physical desired physical form, form, such such as crystalline, as crystalline, powder, powder, solid, solid, liquid,liquid, solution, solution, suspension, suspension, or gel. or gel.

[0020] Unlessotherwise

[0020] Unless otherwisespecified, specified, the the term term "salt" “salt” does does not not mean or imply mean or implyany anyparticular particular

5C 5C

WO wo 2020/167692 PCT/US2020/017555

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.

[0021] In some cases, the composition can include a mixture of one or more beta-

hydroxybutyrate salts and beta-hydroxybutyric acid(s). Providing R-beta-

hydroxybutyrate in its acid form can be beneficial because of its much quicker

absorption response time compared to the salt form. Nonetheless, even though the acid

form by itself is a liquid with extremely low pH and unpalatable taste, when made or

combined with the salt form(s) and where the amount of beta-hydroxybutyric acid is

small relative to the salt form(s), the composition can still form a solid, powder or other

form typical of the salt form(s). In such case, the combined salt and acid form of BHB

has acceptable pH and taste. BHB compositions that include both salt and acid forms

have advantages, such as increased absorption rate, increased bioavailability, lower

electrolyte load, ease of manufacture, significantly improved taste, and reduced need for

citric acid or other edible acids to obtain a composition with neutral or acidic pH. It will

be appreciated that beneficial effects can also be provided using a mixture of BHB salt(s)

and/or ester(s) and the acid form(s) of BHB, BHB.

[0022] 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).

[0023] 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 a

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).

[0024] 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

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.

[0025] 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.

[0026] 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.

[0027] By way of example, if 100 molar equivalents of beta-hydroxybutyrate mixed salt-

acid composition in dry powder form 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

WO wo 2020/167692 PCT/US2020/017555 PCT/US2020/017555

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-

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 solution pH.

[0028] Whether beta-hydroxybutyrate is the R- or S-enantiomer depends on the

tetrahedral orientation of the hydroxy (or oxy group in the case of an ester) on the 3-

carbon (beta-carbon) in relationship to the planar carboxyl group.

[0029] Beta-hydroxybutyrate, typically R-beta-hydroxybutyrate, which is the

endogenous form, 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".

[0030] 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.

[0031] 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.

[0032] 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

(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).

[0033] Another dosage form that can be used to provide a unit dose of composition or

WO wo 2020/167692 PCT/US2020/017555

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.

[0034] 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.

[0035] 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.

[0036] "Ketosis" as used herein refers to a subject having blood ketone levels 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

WO wo 2020/167692 PCT/US2020/017555

nonpathological "mild ketosis" or "therapeutic ketosis."

[0037] 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 bodies. 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." 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.

[0038] The term "short chain triglycerides" (SCT) refers to molecules having a glycerol

backbone attached to three medium chain fatty acids. Short chain fatty acids can range

from 2 to 5 carbon atoms in length. Exemplary short chain fatty acids are acetic acid,

propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid. An

example SCT is tributyrin.

[0039] The term "medium chain triglycerides" (MCT) refers to molecules having a

glycerol backbone attached to three medium chain fatty acids. Medium chain fatty acids

can range from 6 to 12 carbon atoms in length, and more likely 8 to 10 carbon atoms in

length. Exemplary fatty acids are caprylic acid, also known as octanoic acid, comprising

8 carbon molecules, and capric acid, also known as decanoic acid, comprising 10 carbon

molecules. MCTs, medium chain fatty acids, and mono- and di-glycerides are ketone

body precursors that can provide an additional source for the production of ketone bodies

independent of beta-hydroxybutyrate.

[0040] The term "long chain triglycerides" (LCT) refers to molecules having a glycerol

backbone attached to three medium chain fatty acids. Long chain fatty acids can be

greater than 12 carbon atoms in length.

[0041] 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.

II. II. Non-Racemic Beta-Hydroxybutyrate Compositions

[0042] Compositions for increasing ketone body level in a subject, including promoting

and/or sustaining ketosis, comprise a non-racemic mixture of R-beta-hydroxybutyrate

and and S-beta-hy droxy butyrate enriched S-beta-hydroxybutyrate withwith enriched the the R- enantiomer (i.e., (i.e., R- enantiomer more than 50% than more and 50% and

WO wo 2020/167692 PCT/US2020/017555 PCT/US2020/017555

less than 100% by enantiomeric equivalents of R-beta-hydroxybutyrate and less than

50% and more than 0% by enantiomeric equivalents of S-beta-hydroxybutyrate).

[0043] In some embodiments, the non-racemic mixture of R-beta-hy droxybutyrateand R-beta-hydroxybutyrate and

S-beta-hydroxybutyrate contains 50.5% to 99.5%, 51% to 99%, 52% to 98%, 53% to

97%, 55% to 95%, 55% to 89%, 57% to 87%, or 60% to 80% by enantiomeric equivalents equivalentsofof thethe R-beta-hy droxy butyrate enantiomer R-beta-hydroxybutyrate and 49.5% enantiomer and to 0.5%, 49.5% to49% to 1%, 0.5%, 49% to 1%,

48% to 2%, 47% to 3%, 45% to 5%, 45% to 11%, 43% to 13%, 41% to 15%, or 40% to

20% by enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer.

[0044] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate

contains more of the R-beta-hydroxybutyrate enantiomer, the endogenous form produced

by a mammal, than the S-beta-hydroxybutyrate enantiomer in order to provide a greater

and/or faster ketogenic effect compared to a racemic mixture. Because the R-beta-

hydroxybutyrate enantiomer is endogenously produced by a mammal during ketosis,

administering the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer toto a a subject subject provides provides anan additional additional

quantity and/or increased blood plasma level that can be immediately utilized by the

body, such as for producing energy (e.g., as an alternative energy source to glucose),

compared to a racemic mixture of R,S-beta-hydroxybutyrate (aka DL-beta- hydroxybutyrate). The presence of the S-enantiomer can modulate and extend this effect.

[0045] Contrary to conventional wisdom to minimize or eliminate S-beta-

hydroxybutyrate, which is not endogenously produced by a mammal and is believed to

be unnatural and potentially harmful, the non-racemic mixture contains a significant

quantity of the S-beta-hydroxybutyrate enantiomer in order to produce one or more

desired effects in the mammal. For example, administering S-beta-hydroxybutyrate along

with with R-beta-hy droxy butyrate can R-beta-hydroxybutyrate result can in at result in least one of: at least one(1) increased of: endogenous (1) increased endogenous

production of R-beta-hy droxybutyrateand R-beta-hydroxybutyrate andacetoacetate; acetoacetate;(2) (2)endogenous endogenousconversion conversionof of

the S-beta-hydroxybutyrate into one or both of R-beta-hydroxybutyrate and acetoacetate;

(3) endogenous conversion of the S-beta-hy droxy butyrate S-beta-hydroxybutyrate into into fatty fatty acids acids and and sterols; sterols; (4) (4)

prolonged ketosis; (5) metabolism of the S-beta-hydroxybutyrate independent of

conversion to R-beta-hy droxy butyrate R-beta-hydroxybutyrate and/or and/or acetoacetate; acetoacetate; (6) (6) increased increased fetal 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.

[0046] The non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be used, for example, to produce one or more desired effects in the subject, including but not 20 Jun 2025 2020222897 20 Jun 2025 can be used, for example, to produce one or more desired effects in the subject, including but not limited to, limited to, appetite appetite suppression, weightloss, suppression, weight loss, fat fat loss, loss, reduced reduced blood bloodglucose glucose level,improved level, improved mental alertness, mental alertness, increased increased physical physical energy, improvedcognitive energy, improved cognitivefunction, function,reduction reductioninintraumatic traumatic brain injury brain , reduction injury, reduction in in effect effectof ofdiabetes, diabetes,improvement of neurological improvement of neurological disorder, disorder, reduction reduction of of 5 cancer, 5 cancer, reduction reduction of inflammation, of inflammation, anti-aging, anti-aging, antiglycation, antiglycation, reduction reduction in epileptic in epileptic seizure,seizure, improvedmood, improved mood, increased increased strength,increased strength, increasedmuscle muscle mass, mass, or or improved improved bodybody composition. composition.

[0047] Thecomposition composition may include a nutritionallyororpharmaceutically pharmaceutically acceptable carrier. 2020222897

[0047] The may include a nutritionally acceptable carrier.

[0048] R-beta-hydroxybutyrate TheR-beta-hydroxybutyrate

[0048] The andand S-beta-hydroxybutyrate S-beta-hydroxybutyrate can can be provided be provided in various in various forms, forms,

such assalts such as saltsand/or and/or esters, esters, together together withwith a quantity a quantity ofacid of free freeform(s). acid form(s). Theenantiomer The percent percent enantiomer 10 10 equivalents for each equivalents for eachofofR-beta-hydroxybutyrate R-beta-hydroxybutyrateand and S-beta-hydroxybutyrate S-beta-hydroxybutyrate is defined is defined by theby the

molar quantity molar quantity of of either either R-beta-hydroxybutyrate R-beta-hydroxybutyrateororS-beta-hydroxybutyrate S-beta-hydroxybutyrate divided divided by total by the the total combinedmolar combined molar quantitiesofofR-beta-hydroxybutyrate quantities R-beta-hydroxybutyrateand and S-beta-hydroxybutyrate. S-beta-hydroxybutyrate. The amounts The amounts

of any cations of any cations forming formingsalts saltsand/or and/oralcohols alcoholsforming forming esters esters areare excluded excluded and and do count do not not count in in determiningthe determining the percent percent enantiomeric enantiomericequivalents equivalentsfor foreach eachof of R-beta-hydroxybutyrate R-beta-hydroxybutyrate and and S-beta- S-beta-

15 hydroxybutyrate. 15 hydroxybutyrate. For For example, example, the the weight weight contributions contributions of cations, of cations, alcohols,ororcomplexing alcohols, complexing agents agents

can be factored in so as to not tip the scale relative to enantiomeric equivalents of R-BHB and S- can be factored in so as to not tip the scale relative to enantiomeric equivalents of R-BHB and S-

BHB. BHB.

[0049] In order

[0049] In order to to not not overload the composition overload the withR-beta-hydroxybutyrate composition with R-beta-hydroxybutyrateandand a high a high amount amount

of precursor of precursor that thatisisreadily converted readily convertedtoto R-beta-hydroxybutyrate, R-beta-hydroxybutyrate,namely namely the the mono-ester of R-1,3- mono-ester of R-1,3- 20 butanediol ?O butanediol and and R-beta-hydroxybutyrate R-beta-hydroxybutyrate (i.e., (i.e., (3R)-hydroxybutyl (3R)-hydroxybutyl (3R)-hydroxybutyrate (3R)-hydroxybutyrate mono- mono- ester), the ester), thenon-racemic non-racemic mixture of R-beta-hydroxybutyrate mixture of R-beta-hydroxybutyrate and and S-beta-hydroxybutyrate S-beta-hydroxybutyrate shall shall not not

contain contain more than 88%, more than 88%,oror87%, 87%, or or 86%, 86%, or 85% or 85% by enantiomeric by enantiomeric equivalents equivalents of (3R)- of (3R)-

hydroxybutyl(3R)-hydroxybutyrate hydroxybutyl (3R)-hydroxybutyrate mono-ester. mono-ester.

[0050] In some

[0050] In someembodiments, embodiments, the the non-racemic non-racemic mixture mixture of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and S-beta- and S-beta-

25 hydroxybutyrate 25 hydroxybutyrate is provided is provided in a composition in a composition that includes that includes a dietetically a dietetically or pharmaceutically or pharmaceutically

acceptable carrier. Examples acceptable carrier. include Examples include powders, powders, liquids, liquids, tablets, tablets, capsules, capsules, food food products, products, foodfood

additives, beverages, additives, beverageadditives, beverages, beverage additives, candies, candies,suckers, suckers,pastilles, pastilles, food supplements,sprays, food supplements, sprays, injectables, and suppositories. injectables, and suppositories.

[0051] In some

[0051] In someembodiments, embodiments, the the non-racemic non-racemic mixture mixture of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and S-beta- and S-beta-

30 hydroxybutyrate 30 hydroxybutyrate can be provided can be provided as a salt,as a salt, such such as one as one or more or more salts saltsmetals, of alkali of alkali metals, alkaline alkaline earth earth

metals, transition metals, amino acids, or metabolites of amino metals, transition metals, amino acids, or metabolites of amino

12

WO wo 2020/167692 PCT/US2020/017555

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 R-beta-hydroxybutyric acid and/or free S-

beta-hydroxybutyric acid.

[0055] In the case where the non-racemic mixture contains a high amount of the R-

enantiomer relative to the S-enantiomer, it is possible to use a higher ratio of free S-beta-

hydroxybutyric acid relative to S-beta-hydroxybutyrate salt and still obtain a

composition having neutral or other desired pH. That is, even if the relative amount of S-

beta-hydroxybutyric acid is high relative to the S-beta-hydroxybutyrate salt, the overall

amount of acid can be relatively small if the amount of R-beta-hydroxybutyrate salt is

high.

[0056] In other embodiments, the non-racemic mixture can include one or more ester

forms of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate in combination with a

relatively relativelyminor amount minor of the amount acid acid of the form(s) of R-beta-hy form(s) droxybutyrate and/or S-beta- of R-beta-hydroxybutyrate and/or S-beta-

hydroxybutyrate. In yet other embodiments, the non-racemic mixture can include both

salt and ester forms of R-beta-hy droxy butyrate R-beta-hydroxybutyrate and and S-beta-hydroxybutyrate S-beta-hydroxybutyrate inin

combination with a relatively minor amount of the acid form(s) of R-beta- hydroxybutyrate and/or S-beta-hydroxybutyrate.

[0057] In some embodiments, the composition may include 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. The composition may include 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. Though less preferred, the composition may include at least one

long chain fatty acid having more than 12 carbons, or a mono-, di- or triglyceride of the

long chain fatty acid,

[0058] Examples of short chain fatty acids include acetic acid, propionic acid, butyric

acid, isobutyric acid, valeric acid, and isovaleric acid. Examples of medium chain fatty

acids include caproic acid, caprylic acid, capric acid, and lauric acid. 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.

[0059] 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

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WO wo 2020/167692 PCT/US2020/017555

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.

[0060] The administration of a non-racemic mixture of R-beta-hydroxybutyrate and S-

beta-hydroxybutyrate results in elevated and sustained blood levels of ketone bodies,

thereby exploiting the metabolic and physiological advantages of sustained ketosis.

Raising the levels of ketone bodies in the blood 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 non-racemic mixture of R-

beta-hydroxybutyrate and S-beta-hydroxybutyrate 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

therapeutically effective amount of vitamin D3. VitaminDD3 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 is included D is included in in an an amount amount such such that that an an average average daily daily dose dose of of the the ketogenic ketogenic composition 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. Other additives include metabolites that that enhance enhancethe theeffect effectorortransport transportofofketone ketonebodies bodies into mitochondria, caffeine, 20 Jun 2025 2020222897 20 Jun 2025 metabolites into mitochondria, caffeine, theobromine,and theobromine, andnootropics, nootropics,such suchasasL-alpha glycerylphosphorylcholine L-alphaglycerylphosphorylcholine (“alpha ("alpha GPC”). GPC").

[0063] Thecomposition

[0063] The composition may may include include flavoring flavoring agents agents that that help help mask mask the the otherwise otherwise poorpoor taste taste of of

beta-hydroxybutyratecompounds. beta-hydroxybutyrate compounds. These These include include essential essential oils, oils, suchsuch as peppermint, as peppermint, natural natural and and 5 artificialsweeteners, 5 artificial sweeteners,and andother otherflavorants flavorantsknown knownin in theart. the art.

[0064] In some

[0064] In someembodiments, embodiments, ketogenic ketogenic compositions compositions may may further further include include one one or more or more additional additional 2020222897

components configured components configured to to lower lower the the hygroscopicity hygroscopicity of composition. of the the composition. For example, For example, various various

anticaking agents, flow anticaking agents, agents, and/or flow agents, and/or moisture absorbers, in moisture absorbers, in types types and and amounts amountsthat thatare aresafe safe for for consumption, may consumption, may be be included. included. Such Such additional additional components components may include one may include one or or more more of of an an 10 aluminosilicate, 10 aluminosilicate, ferrocyanide, ferrocyanide, carbonate carbonate or bicarbonate or bicarbonate salt,salt, silicate silicate (e.g.,sodium (e.g., sodium or calcium or calcium

silicate), silicate), silica, silica,phosphate salt (e.g., phosphate salt (e.g., di- di- or or tricalcium phosphate), tricalcium phosphate), talc,powdered talc, powdered cellulose, cellulose, calcium calcium

carbonate, and carbonate, and thethe like. like.

III. Administration III. Administration

[0065] In some

[0065] In someembodiments, embodiments, the the compositions compositions disclosed disclosed hereinherein can becan beinused used in a for a method method for 15 increasing 15 increasing ketone ketone body body level,level, including including promoting promoting and/or sustaining and/or sustaining ketosis, ketosis, in in a subject a subject comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective comprising administering to a subject in need thereof a nutritionally or pharmaceutically effective

amount ofone amount of oneor or more morecompositions compositions disclosedherein. disclosed herein.Examples Examplesof of beneficialeffects beneficial effectsof of increasing increasing ketone body level, including promoting and/or sustaining ketosis, in a subject include one or more ketone body level, including promoting and/or sustaining ketosis, in a subject include one or more

of appetite suppression, of appetite suppression, weight weightloss, loss,fat fatloss, loss, reduced reducedblood blood glucose glucose level, level, improved improved mental mental

20 alertness,increased ?O alertness, increased physical physical energy, energy, improved improved cognitive cognitive function, function, reduction reduction in traumatic in traumatic brainbrain

injury, reductioninineffect injury, reduction effectofofdiabetes, diabetes, improvement improvement of neurological of neurological disorder,disorder, reduction reduction of cancer, of cancer,

reduction of reduction of inflammation, inflammation,anti-aging, anti-aging,antiglycation, antiglycation,reduction reduction in in epilepticseizure, epileptic seizure,improved improved mood,increased mood, increasedstrength, strength, increased increased muscle musclemass, mass,ororimproved improved body body composition. composition.

[0066]

[0066] Administering the non-racemic Administering the non-racemicmixture mixtureof of R-beta-hydroxybutyrate R-beta-hydroxybutyrate and S-beta- and S-beta-

25 hydroxybutyrate 25 hydroxybutyrate in the in the enantiomeric enantiomeric ratios ratios or percentages or percentages disclosed disclosed herein herein provides provides onemore one or or more of increased endogenous of increased endogenous production production of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and acetoacetate; and acetoacetate; endogenous endogenous

conversionofofthetheS-beta-hydroxybutyrate conversion S-beta-hydroxybutyrate into into one one or or ofboth both of R-beta-hydroxybutyrate R-beta-hydroxybutyrate and and acetoacetate; acetoacetate; endogenous conversion endogenous conversion of of thethe S-beta-hydroxybutyrate S-beta-hydroxybutyrate intointo fatty fatty acids acids andand sterols; sterols;

prolongedketosis; prolonged ketosis; metabolism metabolismof of thethe S-beta-hydroxybutyrate S-beta-hydroxybutyrate independent independent of conversion of conversion to R- to R- 30 beta-hydroxybutyrate 30 beta-hydroxybutyrate and/or and/or acetoacetate; acetoacetate; increased increased fetalfetal development; development; increased increased growthgrowth years; years;

reduced endogenous reduced endogenous

16

WO wo 2020/167692 PCT/US2020/017555

production of acetone during ketosis; signaling by the S-beta-hydroxybutyrate that

modulates metabolism of R-beta-hy droxy buty rate R-beta-hydroxybutyrate andand glucose; glucose; antioxidant antioxidant activity; activity; andand

production of acetyl-CoA.

[0067] 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 dose will include an amount of non-racemic mixture of R-

beta-hydroxybutyrate and S-beta-hydroxybutyrate 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.

[0068] In some embodiments, the ketogenic compositions can include or be administered

together with other supplements, such as vitamin D3, vitamins, minerals, D, vitamins, minerals, nootropics, nootropics, and 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.

[0069] In some embodiments, the compositions may further include one or more short

chain fatty acids, medium chain fatty acids, long chain fatty acids, fatty acid esters, or

mono-, di- or triglycerides of short, medium, or long chain fatty acids in order to provide

an additional source of ketone bodies, as discussed herein, for sustaining ketosis for a a

longer period of time compared to the non-racemic mixture of R-beta-hydroxybutyrate

and S-beta-hydroxybutyrate by itself. In some embodiments, the composition is

preferably administered such that the ratio of the non-racemic mixture of R-beta-

hydroxybutyrate and S-beta-hydroxybutyrate to short, medium, or long chain fatty acid

(or ester thereof) ranges from about 4:1 to about 1:4, or from about 2:1 to about 1:2, or

from about 1.5:1 to about 1:1.5.

[0070] In some embodiments, the subject preferably follows a ketogenic diet that

restricts intake of carbohydrates and protein during the period of administration of the

composition. For example, 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

WO wo 2020/167692 PCT/US2020/017555 PCT/US2020/017555

promote and/or sustain a state of ketosis.

[0071] In a preferred embodiment, ketogenic compositions can be administered 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.

[0072] 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.

[0073] 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.

[0074] 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.

IV. Examples

[0075] The following is a description of exemplary non-racemic mixtures of R-beta-

hydroxybutyrate and S-beta-hydroxybutyrate compositions and other ketogenic

compositions useful for raising ketone levels in a subject, including inducing and/or

WO wo 2020/167692 PCT/US2020/017555

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 the standpoint of the examples is the enantiomeric percentages

or ratios of R-beta-hy droxy butyrate R-beta-hydroxybutyrate and and S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

[0076] In some cases, the compositions can be a blend of beta-hydroxybutyrate salts,

blend of beta-hydroxybutyrate esters, blend of beta-hydroxybutyrate salts and esters,

blend of beta-hydroxybutyrate salts and free beta-hydroxybutyric acid(s), blend of beta-

hydroxybutyrate esters and free beta-hydroxybutyric acid(s), or blend of beta-

hydroxybutyrate salts, beta-hydroxybutyrate esters, and free beta-hydroxybutyric acid(s),

to provide a desired electrolyte balance, taste and/or pharmacokinetic response. 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

[0077] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyrate compounds R-beta-hydroxybutyrate compounds with with aa racemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 51% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 49% by

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides

for a longer state of ketosis and/or other benefits as disclosed herein.

[0078] The non-racemic mixture 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

[0079] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 52% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer and 48% by

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as compared to the same dosage of racemic mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other benefits as disclosed herein.

Example 3

[0080] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 53% by

enantiomeric equivalents of the R-beta-hy droxybutyrate enantiomer R-beta-hydroxybutyrate enantiomer and and 47% 47% by by

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides

for a longer state of ketosis and/or other benefits as disclosed herein.

Example 4

[0081] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyratecompounds R-beta-hydroxybutyrate compoundswith withaaracemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 55% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 45% 45% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture. On the other hand, including the S-beta-hydroxybutyrate enantiomer provides

for a longer state of ketosis and/or other benefits as disclosed herein.

Example 5

[0082] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 57% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 43% 43% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixture of Examples 1-4. On the other hand, including the S-

beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

WO wo 2020/167692 PCT/US2020/017555

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example Example 6 6

[0083] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyrate compounds R-beta-hydroxybutyrate compounds with with aa racemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 59% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 41% 41% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-5. On the other hand, including the

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 77 Example

[0084] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyrate compounds R-beta-hydroxybutyrate compounds with with aa racemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 65% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 35% 35% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-6. On the other hand, including the

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 8

[0085]

[0085] AAnon-racemic non-racemicmixture of R-beta-hydroxybutyrate mixture and S-beta-hydroxybutyrate of R-beta-hydroxybutyrate is and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyrate compounds R-beta-hydroxybutyrate compounds with with aa racemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 70% by

enantiomeric equivalents of the R-beta-hy droxybutyrate enantiomer R-beta-hydroxybutyrate enantiomer and and 30% 30% by by

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-7. On the other hand, including the

WO wo 2020/167692 PCT/US2020/017555

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 9

[0086] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 75% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 25% 25% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-8. On the other hand, including the

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 10

[0087] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 80% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 20% 20% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-9. On the other hand, including the

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 11

[0088] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hydroxybutyrate compounds with a racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 85% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 15% 15% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

WO wo 2020/167692 PCT/US2020/017555

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-10. On the other hand, including the

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 12 Example 12

[0089]

[0089] AAnon-racemic non-racemicmixture of R-beta-hydroxybutyrate mixture and S-beta-hydroxybutyrate of R-beta-hydroxybutyrate is and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyratecompounds R-beta-hydroxybutyrate compoundswith withaaracemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide 89% by

enantiomeric equivalents of the R-beta-hy droxy butyrate R-beta-hydroxybutyrate enantiomer enantiomer and and 11% 11% byby

enantiomeric equivalents of the S-beta-hydroxybutyrate enantiomer. Because the non-

racemic mixture includes more of the R-beta-hydroxybutyrate enantiomer, the onset of

ketosis is accelerated for a given dosage as compared to the same dosage of racemic

mixture or the non-racemic mixtures of Examples 1-11. On the other hand, including the

S-beta-hydroxybutyrate enantiomer provides for a longer state of ketosis and/or other

benefits as disclosed herein, as compared to a composition containing 90-100% by

enantiomeric equivalents of the R-beta-hydroxybutyrate enantiomer.

Example 13

[0090] A non-racemic mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate is

prepared by mixing one or more R-beta-hy droxybutyratecompounds R-beta-hydroxybutyrate compoundswith withaaracemic racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate to provide from 90%,

91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 99.5% by enantiomeric

equivalents of the R-beta-hydroxybutyrate enantiomer and 10%, 9%, 8%, 7%, 6%, 5%,

4%, 3%, 2%, 1%, or 0.5% by enantiomeric equivalents of the S-beta-hydroxybutyrate

enantiomer, with the proviso that the non-racemic mixture does not contain more than

88%, or 87%, or 86%, or 85% by enantiomeric equivalents of (3R)-hydroxybutyl (3R)-

hydroxybutyrate mono-ester (i.e., the mono-ester of R-1,3-butanediol and R-beta-

hydroxybutyrate). hydroxybutyrate). Because Because the the non-racemic non-racemic mixture mixture includes includes more more of of the the R-beta- R-beta-

hydroxybutyrate enantiomer, the onset of ketosis is accelerated for a given dosage as

compared to the same dosage of racemic mixture or the non-racemic mixtures of

Examples 1-12.

Example 14

[0091] Any of the foregoing examples is modified by combining the non-racemic

mixture mixtureofofR-beta-hy droxy butyrate andand R-beta-hydroxybutyrate S-beta-hydroxybutyrate with a with S-beta-hydroxybutyrate dietetically or a dietetically or

WO wo 2020/167692 PCT/US2020/017555

pharmaceutically acceptable carrier.

Example Example 15 15

[0092] Any of the foregoing examples is modified by combining the non-racemic

mixture of R-beta-hy droxy butyrate R-beta-hydroxybutyrate and and S-beta-hydroxybutyrate S-beta-hydroxybutyrate with with one one oror more more

medium chain triglycerides and/or one or more medium chain fatty acids and/or one or

more mono- or diglycerides of medium chain fatty acids.

Example Example 16 16

[0093] Any of the foregoing examples is modified by combining the non-racemic

mixture mixtureofofR-beta-hydroxybutyrate and S-beta-hy R-beta-hydroxybutyrate droxy butyrate with one and S-beta-hydroxybutyrate or more with one short or more short

chain triglycerides and/or one or more short chain fatty acids and/or one or more mono-

or diglycerides of short chain fatty acids.

Example 17

[0094] Any of the foregoing examples is modified by combining the non-racemic

mixture of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate with one or more long

chain triglycerides and/or one or more long chain fatty acids and/or one or more mono-

or diglycerides of long chain fatty acids.

Example Example 18 18

[0095] Any of the foregoing examples is modified by combining the non-racemic

mixture of R-beta-hy droxy butyrate R-beta-hydroxybutyrate and and S-beta-hydroxybutyrate S-beta-hydroxybutyrate with with one one oror more more

supplements, such as vitamin D3, vitamins, minerals, D, vitamins, minerals, and and others others known known in in the the art. art.

Example 19

[0096] Any of the foregoing examples is modified by including one or more salts of R-

beta-hydroxybutyrate and S-beta-hydroxybutyrate and at least one of R-beta-

hydroxybutyric acid or S-beta-hydroxybutyric acid to provide a mixture of R- and S-

beta-hydroxybutyrate salts and free R- and/or S-beta-hydroxybutyric acid(s), where the

mixture contains less than 100% of the one or more beta-hydroxybutyrate salts and

greater than 0% of the free beta-hydroxybutyric acid(s), including 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% by molar equivalents of one or

more R-beta-hydroxybutyrate and/or 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%, by molar equivalents of free R-beta- hydroxybutyric acid and/or free S-beta-hydroxybutyric acid.

Example 20

[0097] Anyofofthe theforegoing foregoing examples is modified by including one or esters more esters of R-beta- 20 Jun 2025 2020222897 20 Jun 2025

[0097] Any examples is modified by including one or more of R-beta-

hydroxybutyrateand hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrateandand at at leastone least oneofofR-beta-hydroxybutyric R-beta-hydroxybutyric acid acid or or S- S-

beta-hydroxybutyricacid beta-hydroxybutyric acidtoto provide provideaamixture mixtureofofR-R-and andS-beta-hydroxybutyrate S-beta-hydroxybutyrate ester ester forms forms andand

free free R- R- and/or S-beta-hydroxybutyricacid(s), and/or S-beta-hydroxybutyric acid(s),where wherethe thenon-racemic non-racemic mixture mixture contains contains lessless than than

5 5 100% 100% ofofthe theoneone or or more more beta-hydroxybutyrate beta-hydroxybutyrate esters esters and and greater greater thanthan 0% beta- 0% free free beta- hydroxybutyricacid. hydroxybutyric acid. 2020222897

[0098] Thepresent

[0098] The presentinvention inventionmay maybebeembodied embodied in other in other specificforms specific forms without without departing departing from from its its

spirit spirit or or essential characteristics.The essential characteristics. The described described embodiments embodiments are to beare to be considered considered in all respects in all respects

only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the

10 appended 10 appended claims claims rather rather than than by foregoing by the the foregoing description. description. All changes All changes which which come comethe within within the meaningand meaning andrange rangeofofequivalency equivalencyof of theclaims the claimsare aretotobebeembraced embraced within within theirscope. their scope.

[0099] Throughoutthis

[0099] Throughout thisspecification specificationand andthetheclaims claims which which follow, follow, unless unless the context the context requires requires

otherwise, the word otherwise, the word"comprise", "comprise",andand variations variations such such as as "comprises" "comprises" and and "comprising", "comprising", will be will be

understood understood to to imply imply the inclusion the inclusion of a stated of a stated integerinteger or step or or step groupor ofgroup of orintegers integers ornot steps but steps but not 15 15 the exclusion of any other integer or step or group of integers or steps. the exclusion of any other integer or step or group of integers or steps.

[0100] The

[0100] The reference reference in this in this specification specification to prior to any any prior publication publication (or information (or information derived derived from it), from it),

or to any or to any matter matterwhich whichis is known, known, is not, is not, and and should should nottaken not be be taken as an as an acknowledgment acknowledgment or or admission admission or or anyany form form of suggestion of suggestion thatprior that that that publication prior publication (or information (or information derived derived from it) or from it) or

knownmatter known matterforms formspart partofofthe the common common general general knowledge knowledge in the in the field field of of endeavour endeavour to to which which this this

20 specification ?O specification relates. relates.

25

Theclaims claimsdefining definingthe theinvention invention areare as as follows: 20 Jun 2025

2025 The follows:

2020222897 20 Jun

1. 1. A composition A compositionfor foradministering administeringketone ketonebodies bodiestotoa asubject, subject, comprising: comprising: aa non-racemic mixtureofofR-beta-hydroxybutyrate non-racemic mixture R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate S-beta-hydroxybutyrate containing containing

50.5% 50.5% toto99.5% 99.5%by by enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and 49.5% and 49.5% to 0.5% to by0.5% by

enantiomeric equivalentsof enantiomeric equivalents of S-beta-hydroxybutyrate, S-beta-hydroxybutyrate,wherein wherein thenon-racemic the non-racemic mixture mixture of R-beta- of R-beta-

hydroxybutyrateand andS-beta-hydroxybutyrate S-beta-hydroxybutyrate includes: 2020222897

hydroxybutyrate includes:

at at least least one R-beta-hydroxybutyrate one R-beta-hydroxybutyrate salt; salt;

at at least least one S-beta-hydroxybutyrate one S-beta-hydroxybutyrate salt; salt; and and

at at least least one of R-R-ororS-beta-hydroxybutyric one of S-beta-hydroxybutyricacid, acid, and and whereinthe wherein the composition compositionisisaa powder, powder, whereinthe wherein the non-racemic non-racemicmixture mixturecomprises comprises 75% 75% to to 99%99% by molar by molar equivalents equivalents of combined of combined

R-beta-hydroxybutyrateand R-beta-hydroxybutyrate and S-beta-hydroxybutyrate S-beta-hydroxybutyrate salts salts andand 25%25% to by to 1% 1%molar by molar equivalents equivalents of of R-beta-hydroxybutyricacid R-beta-hydroxybutyric acidand/or and/orS-beta-hydroxybutyric S-beta-hydroxybutyric acid. acid.

2. 2. The composition The compositionofofclaim claim1,1,wherein whereinthethenon-racemic non-racemic mixture mixture contains contains from from 51% 51% to to 99% 99% by enantiomeric by enantiomeric equivalents equivalents of of R-beta-hydroxybutyrate R-beta-hydroxybutyrate and and 49% 49%toto1% 1% by enantiomeric by enantiomeric

equivalents equivalents of of S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

3. 3. The composition The compositionofofclaim claim1 1oror2,2,wherein whereinthethenon-racemic non-racemic mixture mixture contains contains fromfrom 52% 52% to to 98% 98% byby enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate andto 48% and 48% 2% bytoenantiomeric 2% by enantiomeric equivalents equivalents of of S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

4. 4. The composition The compositionofofany anyone oneofofclaims claims1-3, 1-3,wherein whereinthe thenon-racemic non-racemic mixture mixture contains contains from from

53% 53% toto97% 97%by by enantiomeric enantiomeric equivalents equivalents of of R-beta-hydroxybutyrateandand R-beta-hydroxybutyrate 47%47% to by3% by to 3%

enantiomeric equivalentsof enantiomeric equivalents of S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

5. 5. The composition The compositionofofanyany oneone of of claims claims 1-4,1-4, wherein wherein the the non-racemic non-racemic mixture mixture comprises comprises

80% 80% toto99%99% by molar by molar equivalents equivalents of combined of combined R-beta-hydroxybutyrate R-beta-hydroxybutyrate and S-beta- and S-beta-

hydroxybutyratesalts hydroxybutyrate salts and and 20% 20%toto1%1% by by molar molar equivalents equivalents of R-beta-hydroxybutyric of R-beta-hydroxybutyric acid acid and/or and/or

S-beta-hydroxybutyricacid. S-beta-hydroxybutyric acid.

26

20 Jun 2025

6. 6. The composition The compositionofofanyany oneone of of claims claims 1-5,1-5, wherein wherein the the non-racemic non-racemic mixture mixture comprises comprises

90% 90% toto 99% 99%by by molar molar equivalentsof ofcombined equivalents combined R-beta-hydroxybutyrate and R-beta-hydroxybutyrate and S-beta- S-beta- hydroxybutyratesalts hydroxybutyrate salts and and 10% 10%toto1%1% by by molar molar equivalents equivalents of R-beta-hydroxybutyric of R-beta-hydroxybutyric acid acid and/or and/or

S-beta-hydroxybutyricacid. S-beta-hydroxybutyric acid.

7. The composition compositionofofanyany oneone of of claims 1-6,1-6, wherein the the non-racemic mixture comprises 2020222897

2020222897

7. The claims wherein non-racemic mixture comprises

94% 94% toto99%99% by molar by molar equivalents equivalents of combined of combined R-beta-hydroxybutyrate R-beta-hydroxybutyrate and S-beta- and S-beta-

hydroxybutyratesalts hydroxybutyrate salts and and6%6%toto1%1% by by molar molar equivalents equivalents of R-beta-hydroxybutyric of R-beta-hydroxybutyric acid and/or acid and/or

S-beta-hydroxybutyricacid. S-beta-hydroxybutyric acid.

8. 8. The composition The compositionofofany anyone oneofofclaims claims1-7, 1-7,wherein wherein thenon-racemic the non-racemic mixture mixture comprises comprises at at least least one lithium, sodium, one lithium, sodium,potassium, potassium, calcium, calcium, magnesium, magnesium, oracid or amino amino salt acid salt of R-beta- of R-beta-

hydroxybutyrateand/or hydroxybutyrate and/orS-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

9. 9. The composition of any one of claims 1-8, further comprising at least one short chain fatty The composition of any one of claims 1-8, further comprising at least one short chain fatty

acid havingless acid having lessthan than 6 carbons, 6 carbons, or aor a mono-, mono-, di- ordi- or triglyceride triglyceride of the of the atone at least least onechain short short chain fatty fatty

acid. acid.

10. 10. The The composition composition of anyofone anyofone of claims claims 1-9, further 1-9, further comprising comprising at leastatone least one supplement supplement

selected selected from vitamin, mineral, from vitamin, mineral, nootropic, nootropic, and and herbal herbal supplement. supplement.

11. 11. A composition A composition for administering for administering ketone ketone bodies bodies to a to a subject, subject, comprising: comprising:

aa non-racemic mixtureofofR-beta-hydroxybutyrate non-racemic mixture R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate S-beta-hydroxybutyrate containing containing

50.5% 50.5% toto99.5% 99.5%by by enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and 49.5% and 49.5% to 0.5% to by0.5% by

enantiomeric equivalentsof enantiomeric equivalents of S-beta-hydroxybutyrate, S-beta-hydroxybutyrate,wherein wherein thenon-racemic the non-racemic mixture mixture of R-beta- of R-beta-

hydroxybutyrateand hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate includes: includes:

at at least least one R-beta-hydroxybutyrate one R-beta-hydroxybutyrate salt salt or or ester; ester;

at at least least one S-beta-hydroxybutyrate one S-beta-hydroxybutyrate saltester; salt or or ester; and and

at at least least one of R-R-ororS-beta-hydroxybutyric one of S-beta-hydroxybutyricacid, acid, and and whereinthe wherein the composition compositionisisprovided providedasasororin in aa tablet, tablet, capsule, capsule,powder, powder, food food product, product, food food

27

Claims (1)

1. additive, flavoredbeverage, beverage, vitamin fortified beverage, non-alcoholic beverage,beverage, flavored beverage 20 Jun 2025 Jun 2025 additive, flavored vitamin fortified beverage, non-alcoholic 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,

   whereinthe wherein the non-racemic non-racemicmixture mixturecomprises comprises 75% 75% to to 99%99% by molar by molar equivalents equivalents of combined of combined 2020222897 20

   R-beta-hydroxybutyrateand R-beta-hydroxybutyrate and S-beta-hydroxybutyrate S-beta-hydroxybutyrate salts salts andand 25%25% to by to 1% 1%molar by molar equivalents equivalents of of R-beta-hydroxybutyricacid R-beta-hydroxybutyric acidand/or and/orS-beta-hydroxybutyric S-beta-hydroxybutyric acid. acid. 2020222897

   12. 12. The The composition composition of claim of claim 11, wherein 11, wherein the non-racemic the non-racemic mixture mixture contains contains from from 51% to 51% 99% to 99% by enantiomeric by enantiomeric equivalents equivalents of of R-beta-hydroxybutyrate R-beta-hydroxybutyrate and and 49% 49%toto1% 1% by enantiomeric by enantiomeric

   equivalents equivalents of of S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

   13. 13. The The composition composition of claim of claim 11 or 11 12,orwherein 12, wherein the non-racemic the non-racemic mixture mixture comprises comprises 80% to 80% to 99% bymolar 99% by molarequivalents equivalentsofofcombined combined R-beta-hydroxybutyrate R-beta-hydroxybutyrate and S-beta-hydroxybutyrate and S-beta-hydroxybutyrate salts salts

   and 20%toto1%1%bybymolar and 20% molar equivalents equivalents of of R-beta-hydroxybutyric R-beta-hydroxybutyric acid acid and/or and/or S-beta-hydroxybutyric S-beta-hydroxybutyric

   acid. acid.

   14. 14. The The composition composition ofone of any anyofone of claims claims 11-13, 11-13, wherein wherein the non-racemic the non-racemic mixturemixture comprises comprises

   at at least least one lithium, sodium, one lithium, sodium,potassium, potassium,calcium, calcium, magnesium, magnesium, or amino or amino acidof salt acid salt of R-beta- R-beta-

   hydroxybutyrateand/or hydroxybutyrate and/orS-beta-hydroxybutyrate, S-beta-hydroxybutyrate,andand wherein wherein the the composition composition is aispowder. a powder.

   15. 15. The The composition composition ofone of any anyofone of claims claims 11-14,11-14, further further comprising comprising at one at least leastsupplement one supplement selected selected from vitamin, mineral, from vitamin, mineral, nootropic, nootropic, and and herbal herbal supplement. supplement.

   16. 16. A composition A composition for administering for administering ketone ketone bodies bodies to a to a subject, 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; and and

   aa non-racemic mixtureofofR-beta-hydroxybutyrate non-racemic mixture R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate S-beta-hydroxybutyrate containing containing

   50.5% 50.5% toto99.5% 99.5%by by enantiomeric enantiomeric equivalents equivalents of R-beta-hydroxybutyrate of R-beta-hydroxybutyrate and 49.5% and 49.5% to 0.5% to by0.5% by

   28 enantiomeric equivalentsof of S-beta-hydroxybutyrate, S-beta-hydroxybutyrate,wherein wherein thenon-racemic non-racemic mixture of R-beta- 20 Jun 2025 Jun 2025 enantiomeric equivalents the mixture of R-beta- hydroxybutyrateand hydroxybutyrate andS-beta-hydroxybutyrate S-beta-hydroxybutyrate includes: includes: at at least leastone oneR-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate salt or R-beta-hydroxybutyrate ester; R-beta-hydroxybutyrate ester; at at least leastone oneS-beta-hydroxybutyrate salt or S-beta-hydroxybutyrate salt orS-beta-hydroxybutyrate ester; and S-beta-hydroxybutyrate ester; and 2020222897 20 at at least least one of R-R-ororS-beta-hydroxybutyric one of S-beta-hydroxybutyricacid, acid, whereinthe wherein the non-racemic non-racemicmixture mixturecomprises comprises 75% 75% to to 99%99% by molar by molar equivalents equivalents of combined of combined

   R-beta-hydroxybutyrateand andS-beta-hydroxybutyrate S-beta-hydroxybutyrate salts and 25%25% to by 1%molar by molar equivalents of 2020222897

   R-beta-hydroxybutyrate salts and to 1% equivalents of

   R-beta-hydroxybutyricacid R-beta-hydroxybutyric acidand/or and/orS-beta-hydroxybutyric S-beta-hydroxybutyric acid. acid.

   17. 17. A kit A kit forfor administering administering ketone ketone bodies bodies to atosubject, a subject,comprising: comprising: aa composition as in composition as in any one of any one of claims claims 1-16; 1-16; 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, wherein a unit a unit dose dose of theofcomposition the composition contains contains about 0.5 about 0.5 g25tog about g to about of the 25 g of the non- non-

   racemic mixture racemic mixtureofofR-beta-hydroxybutyrate R-beta-hydroxybutyrateandand S-beta-hydroxybutyrate. S-beta-hydroxybutyrate.

   18. 18. The The kit kit of claim of claim 17,17, 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.

   19. 19. TheThe kitkit of of claim1717 claim or or 18,wherein 18, 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.

   20. Use Use 20. of aof a composition composition as inasany in any one one of claims of claims 1-161-16 in the in the manufacture manufacture of a of a medicament medicament for for increasing blood ketone increasing blood ketonelevel level in in aa subject, subject, wherein increasingblood wherein increasing bloodketone ketonelevel levelininthe thesubject subject causes one or causes one or more moreof: of: appetite appetite suppression, suppression, weight weightloss, loss, fat fat loss, loss, reduced bloodglucose reduced blood glucoselevel, level, improved mental improved mental alertness,increased alertness, increased physical physical energy, energy, improved improved cognitive cognitive function, function, reduction reduction

   in in traumatic traumatic brain brain injury, injury,reduction reduction in ineffect effectofof diabetes, improvement diabetes, of neurological improvement of disorder, neurological disorder,

   reduction of reduction of cancer, cancer, reduction of inflammation, reduction of anti-aging,antiglycation, inflammation, anti-aging, antiglycation,reduction reductionininepileptic epileptic seizure, seizure, improved mood,increased improved mood, increasedstrength, strength, increased increased muscle musclemass, mass,ororimproved improved body body

   composition. composition.

   29

   21 -A–Amethod method for for increasing bloodblood ketoneketone level in a subject, comprising administering a 20 Jun 2025 2020222897 20 Jun 2025

   21 increasing level in a subject, comprising administering a

   compositionaccording composition accordingtotoany anyone oneofofclaims claims1-16 1-16 toto thesubject, the subject,wherein whereinincreasing increasingblood bloodketone ketone level level causes one or causes one or more moreof: of:appetite appetitesuppression, suppression,weight weightloss, loss,fat fatloss, loss, reduced reducedblood bloodglucose glucose level, level, improved mental improved mental alertness, alertness, increased increased physical physical energy, energy, improved improved cognitive cognitive function,function,

   reduction in reduction in traumatic brain injury, traumatic brain injury, reduction reduction in in effect effectofofdiabetes, diabetes,improvement of neurological improvement of neurological

   disorder, reduction disorder, reduction of of cancer, cancer, reduction of inflammation, reduction of inflammation,anti-aging, anti-aging, antiglycation, antiglycation, reduction reduction in in epileptic epileptic seizure, seizure,improved mood,increased increasedstrength, strength,increased increasedmuscle musclemass, mass, or or improved bodybody 2020222897

   improved mood, improved

   composition. composition.

   30