Search

US-12622889-B2 - S-β-hydroxybutyrate esters for improving metabolic function

US12622889B2US 12622889 B2US12622889 B2US 12622889B2US-12622889-B2

Abstract

Compositions for improving metabolic function in a subject include optically pure S-beta-hydroxybutyrate or non-racemic mixtures enriched with the S-enantiomer. S-beta-hydroxybutyrate in pure or enriched form provides energy to the heart, dilates the arteries, decreases blood pressure and systemic vascular resistance, and increases cardiac output. S-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. S-Beta-hydroxybutyrate salts are more slowly absorbed and utilized by the body and provide one or more electrolytes. S-Beta-hydroxybutyrate esters provide more controlled release without adding electrolytes. Compositions for improving heart function in a subject may contain a dietetically or pharmaceutically acceptable carrier and optically pure S-beta-hydroxybutyrate or non-racemic mixture enriched with S-beta-hydroxybutyrate, wherein the compositions contain from about 50.5% to 100% by enantiomeric equivalents of S-beta-hydroxybutyrate and from about 49.5% to 0% by enantiomeric equivalents of R-beta-hydroxybutyrate.

Inventors

  • Gary Millet
  • Ryan Lowery
  • Jacob Wilson
  • Terry LaCore

Assignees

  • AXCESS GLOBAL SCIENCES, LLC

Dates

Publication Date
20260512
Application Date
20250829

Claims (20)

  1. 1 . A composition for improving metabolic function in a subject, comprising: one or more esters of optically pure S-beta-hydroxybutyrate or one or more esters of a non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate containing more than 50% and less than 100% by enantiomeric equivalents of at least one S-beta-hydroxybutyrate ester and less than 50% and more than 0% by enantiomeric equivalents of at least one R-beta-hydroxybutyrate ester.
  2. 2 . The composition of claim 1 , wherein the composition comprises one or more esters of S-beta-hydroxybutyrate and at least one component selected from the group consisting of ethanol, 1-propanol, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, glycerin, S-beta-hydroxybutyrate R-beta-hydroxybutyrate, acetoacetate, dimers, trimers, oligomers, or polyesters containing repeating units of beta-hydroxybutyrate, and complex oligomers or polymers of beta-hydroxybutyrate and one or more carboxylic acids selected from lactic acid, citric acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, malic acid, succinic acid, and fumaric acid.
  3. 3 . The composition of claim 1 , wherein the composition comprises one or more esters of S-beta-hydroxybutyrate and at least one component selected from the group consisting of altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, glycerol, gulose, idose, lactose, lyxose, mannose, ribitol, ribose, ribulose, sucrose, talose, threose, xylitol, xylose, galactosamine, glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol, and threitol.
  4. 4 . The composition of claim 1 , wherein the composition comprises a mixture of S-beta-hydroxybutyrate ester and at least one of S-beta-hydroxybutyric acid or S-beta-hydroxybutyrate salt.
  5. 5 . The composition of claim 1 , wherein the composition comprises a non-racemic mixture that contains 50.5% to 99.5% by enantiomeric equivalents of S-beta-hydroxybutyrate ester and 49.5% to 0.5% by enantiomeric equivalents of R-beta-hydroxybutyrate ester, or 51% to 99% by enantiomeric equivalents of S-beta-hydroxybutyrate ester and 49% to 1% by enantiomeric equivalents of R-beta-hydroxybutyrate ester, or 52% to 98% by enantiomeric equivalents of S-beta-hydroxybutyrate ester and 48% to 2% by enantiomeric equivalents of R-beta-hydroxybutyrate ester.
  6. 6 . The composition of claim 1 , further comprising an ester of optically pure S-1,3-butanediol or an ester of a non-racemic mixture enriched with S-1,3-butanediol relative to R-1,3-butanediol.
  7. 7 . The composition of claim 1 , wherein the composition further comprises at least one medium chain fatty acid having 6 to 12 carbons or ester thereof.
  8. 8 . The composition of claim 1 , wherein the composition further comprises at least one short chain fatty acid having less than 6 carbons, or a mono-, di- or triglyceride of the at least one short chain fatty acid.
  9. 9 . The composition of claim 1 , wherein the composition improves brain function in the subject.
  10. 10 . The composition of claim 1 , wherein the composition improves heart function in the subject.
  11. 11 . The composition of claim 1 , wherein the composition improves organ function in the subject.
  12. 12 . A kit for administering the composition of claim 1 to a subject, comprising: a container in which the composition is placed, wherein the container is selected from the group consisting of carton, box, can, jar, bag, pouch, bottle, jug, liquid squeeze bottle with integrated measuring device, and keg; and a measuring device configured to hold therein a unit dose, or fraction thereof, of the composition, wherein the measuring device is selected from the group consisting of cup, scoop, syringe, dropper, spatula, spoon, and colonic irrigation device.
  13. 13 . A composition for improving metabolic function in a subject, comprising: one or more esters of optically pure S-beta-hydroxybutyrate or one or more esters of a non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate containing more than 50% and less than 100% by enantiomeric equivalents of at least one S-beta-hydroxybutyrate ester and less than 50% and more than 0% by enantiomeric equivalents of at least one R-beta-hydroxybutyrate ester, wherein the composition is provided as or in a tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin fortified beverage additive, non-alcoholic beverage additive, candy, sucker, pastille, food supplement, flavored mouth spray, or suppository.
  14. 14 . The composition of claim 13 , wherein the composition comprises one or more esters of S-beta-hydroxybutyrate and at least one component selected from the group consisting of ethanol, 1-propanol, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, glycerin, S-beta-hydroxybutyrate R-beta-hydroxybutyrate, acetoacetate, dimers, trimers, oligomers, or polyesters containing repeating units of beta-hydroxybutyrate, and complex oligomers or polymers of beta-hydroxybutyrate and one or more carboxylic acids selected from lactic acid, citric acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, malic acid, succinic acid, and fumaric acid.
  15. 15 . The composition of claim 13 , wherein the composition comprises one or more esters of S-beta-hydroxybutyrate and at least one component selected from the group consisting of altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, glycerol, gulose, idose, lactose, lyxose, mannose, ribitol, ribose, ribulose, sucrose, talose, threose, xylitol, xylose, galactosamine, glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol, and threitol.
  16. 16 . The composition of claim 13 , wherein the composition improves metabolic function of at least one of the subject's brain, heart, or other organ.
  17. 17 . A composition for improving metabolic function in a subject, comprising: a dietetically or pharmaceutically acceptable carrier selected from the group consisting of tablet, capsule, powder, food product, food additive, flavored beverage, vitamin fortified beverage, non-alcoholic beverage, flavored beverage additive, vitamin fortified beverage additive, non-alcoholic beverage additive, candy, sucker, pastille, food supplement, flavored mouth spray, and suppository; and one or more esters of optically pure S-beta-hydroxybutyrate or one or more esters of a non-racemic mixture of S-beta-hydroxybutyrate and R-beta-hydroxybutyrate containing more than 50% and less than 100% by enantiomeric equivalents of at least one S-beta-hydroxybutyrate ester and less than 50% and more than 0% by enantiomeric equivalents of at least one R-beta-hydroxybutyrate ester.
  18. 18 . The composition of claim 17 , wherein the composition comprises one or more esters of S-beta-hydroxybutyrate and at least one component selected from the group consisting of ethanol, 1-propanol, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, glycerin, S-beta-hydroxybutyrate R-beta-hydroxybutyrate, acetoacetate, dimers, trimers, oligomers, or polyesters containing repeating units of beta-hydroxybutyrate, and complex oligomers or polymers of beta-hydroxybutyrate and one or more carboxylic acids selected from lactic acid, citric acid, quinic acid, shikimic acid, salicylic acid, tartaric acid, malic acid, succinic acid, and fumaric acid.
  19. 19 . The composition of claim 17 , wherein the composition comprises one or more esters of S-beta-hydroxybutyrate and at least one component selected from the group consisting of altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, glycerol, gulose, idose, lactose, lyxose, mannose, ribitol, ribose, ribulose, sucrose, talose, threose, xylitol, xylose, galactosamine, glucosamine, mannosamine, N-acetylglucosamine, mannitol, sorbitol, and threitol.
  20. 20 . The composition of claim 17 , wherein the composition improves metabolic function of at least one of the subject's brain, heart, or other organ.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This Application is a continuation-in-part of U.S. application Ser. No. 19/221,260, filed May 28, 2025, which is a continuation of U.S. application Ser. No. 18/592,262, filed Feb. 29, 2024, now U.S. Pat. No. 12,329,734, which is a continuation-in-part of U.S. application Ser. No. 18/218,519, filed Jul. 5, 2023, now U.S. Pat. No. 11,944,598, which is a continuation-in-part of U.S. patent application Ser. No. 17/555,724, filed Dec. 20, 2021, now U.S. Pat. No. 11,786,499, which is a continuation of U.S. patent application Ser. No. 17/130,498, filed Dec. 22, 2020, now U.S. Pat. No. 11,202,769, which is a continuation-in-part of U.S. patent application Ser. No. 16/783,886, filed Feb. 6, 2020, now U.S. Pat. No. 11,185,518, which is a continuation-in-part of U.S. patent application Ser. No. 16/272,192, filed Feb. 11, 2019, now U.S. Pat. No. 10,596,130, which is a continuation-in-part of U.S. patent application Ser. No. 16/224,485, filed Dec. 18, 2018, now U.S. Pat. No. 10,596,128, which is a division of U.S. patent application Ser. No. 15/936,849, filed Mar. 27, 2018, now U.S. Pat. No. 10,245,243, which claims the benefit of U.S. Provisional Application No. 62/607,578, filed Dec. 19, 2017, which are incorporated herein by reference in their entirety. This Application is also a continuation-in-part of U.S. application Ser. No. 19/096,389, filed Mar. 31, 2025, which is a continuation of U.S. application Ser. No. 18/977,541, filed Dec. 11, 2024, now U.S. Pat. No. 12,350,243, which is a continuation of U.S. application Ser. No. 18/219,556, filed Jul. 7, 2023, now U.S. Pat. No. 12,251,362, which is a continuation of U.S. patent application Ser. No. 17/367,206, filed Jul. 2, 2021, now U.S. Pat. No. 12,109,182, which is a continuation-in-part of U.S. patent application Ser. No. 15/491,924, filed Apr. 19, 2017, now U.S. Pat. No. 11,173,138, which claims the benefit of U.S. Provisional Application No. 62/324,798, filed Apr. 19, 2016, which are incorporated herein by reference in their entirety. BACKGROUND 1. Field of the Invention The invention relates to S-beta-hydroxybutyrate esters, non-racemic beta-hydroxybutyrate esters enriched with S-beta-hydroxybutyrate esters relative to R-beta-hydroxybutyrate esters, and compositions and methods for improving metabolic function. 2. Related Technology In periods of fasting, extreme exercise, and/or low carbohydrate consumption, glucose and glycogen stores in the body are rapidly used and can become quickly depleted. Failure to replenish glucose stores as they become depleted causes the body to metabolically shift to the creation and use of ketone bodies for energy (“ketosis”). Ketone bodies can be used by cells of the body as a fuel to satisfy the body's energy needs, including the brain and heart. During prolonged fasting, for example, blood ketone levels can increase to 2-3 mmol/L or more. It is conventionally understood that when blood ketones rise above 0.5 mmol/L, the heart, brain and peripheral tissues are using ketone bodies (e.g., beta-hydroxybutyrate and acetoacetate) as the primary fuel source. This condition is referred to as ketosis. At blood levels between 1.0 mmol/L and 3.0 mmol/L the condition is called “nutritional ketosis.” 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. 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., “β-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. The metabolism of ketone bodies is associated with several beneficial effects, 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 have beneficial impacts on physical, cognitive health, and psychological health, and a long-term impact on health with respect to common avoidable diseases such as obesity, cardiovascular disease, neurodegenerative diseases, diabetes, and cancer. 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 ba