Hydroxybutyrate ester and medical use thereof
Inventors
Clarke, Kieran • Veech, Richard Lewis
Assignees
Oxford University Innovation Ltd • US Department of Health and Human Services
Publication Number
US-10051880-B2
Publication Date
2018-08-21
Expiration Date
2029-04-16
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Abstract
A compound which is 3-hydroxybutyl 3-hydroxybutyrate enantiomerically enriched with respect to (3R)-hydroxybutyl (3R)-hydroxybutyrate of formula (I) is an effective and palatable precursor to the ketone body (3R)-hydroxybutyrate and may therefore be used to treat a condition which is caused by, exacerbated by or associated with elevated plasma levels of free fatty acids in a human or animal subject, for instance a condition where weight loss or weight gain is implicated, or to promote alertness or improve cognitive function, or to treat, prevent or reduce the effects of neurodegeneration, free radical toxicity, hypoxic conditions or hyperglycaemia.
Core Innovation
The invention provides a compound, 3-hydroxybutyl 3-hydroxybutyrate, enantiomerically enriched with respect to the (3R)-hydroxybutyl (3R)-hydroxybutyrate isomer, which serves as an effective and palatable precursor to the ketone body (3R)-hydroxybutyrate. This compound elevates blood levels of (3R)-hydroxybutyrate upon oral ingestion, delivering ketone bodies quickly and sustaining their presence in the blood due to its favorable pharmacokinetic profile.
The invention addresses the problem that direct administration of ketone bodies like (R)-3-hydroxybutyrate or acetoacetate is impractical and potentially dangerous due to risks including acidosis and sodium overload. Existing derivatives, such as those described in prior art WO2004/108740, lack the palatability and pharmacokinetic advantages of this specific enriched enantiomer. The invention further solves clinical challenges associated with conditions caused or exacerbated by elevated plasma levels of free fatty acids, cognitive dysfunction, neurodegeneration, and metabolic and hypoxic conditions.
Moreover, the enantiomerically enriched compound reduces plasma levels of free fatty acids and modulates appetite centers in the brain by increasing anorexigenic neuropeptides and malonyl CoA, thus offering therapeutic benefits for conditions involving weight regulation. It also promotes brain metabolic efficiency and increases levels of neuropeptides such as BDNF and CART, supporting cognitive function improvement and neurodegeneration inhibition. The compound is suitable for formulation into ingestible compositions including dietary supplements, medicaments, foods, and beverages.
Claims Coverage
The patent contains three claims including one independent claim focusing on the compound and two dependent claims related to compositions comprising the compound.
Enantiomerically enriched hydroxybutyl hydroxybutyrate compound
An ingestible compound which is 3-hydroxybutyl 3-hydroxybutyrate enantiomerically enriched to between 90% and 99% with respect to (3R)-hydroxybutyl (3R)-hydroxybutyrate of formula (I).
Composition for rehydration comprising the compound
A composition for rehydration comprising the compound of 3-hydroxybutyl 3-hydroxybutyrate enantiomerically enriched as above, water, and a sugar carbohydrate.
Enantiomeric enrichment range specification
The compound is further specified to be enantiomerically enriched to 90-95%."
The claims primarily cover the specific enantiomerically enriched compound of 3-hydroxybutyl 3-hydroxybutyrate and its inclusion in compositions such as rehydration drinks, emphasizing the degree of enantiomeric enrichment as a key inventive feature.
Stated Advantages
The (3R,3R′) enantiomer is palatable and less bitter tasting than other ketone bodies, making it particularly suited for oral administration.
The compound achieves rapid and sustained elevation of blood (3R)-hydroxybutyrate levels, providing a favorable pharmacokinetic profile.
The compound effectively reduces plasma levels of free fatty acids, which is beneficial in treating various metabolic and degenerative conditions.
It suppresses appetite by increasing anorexigenic neuropeptides and malonyl CoA in the brain, thereby supporting weight management.
It enhances brain metabolic efficiency and elevates neuropeptides that promote alertness and cognitive function, such as BDNF and CART.
Documented Applications
Treatment of conditions caused by, exacerbated by, or associated with elevated plasma levels of free fatty acids, including neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's chorea), hypoxic states (stroke, myocardial infarction), insulin resistant states (diabetes, obesity), and inflammatory diseases.
Use in treating conditions where weight loss or gain is implicated, such as obesity, overweight states, and maintaining a healthy weight by suppressing appetite and decreasing fat to lean muscle ratio.
Promotion of alertness and improvement of cognitive function, including treatment of cognitive dysfunction.
Treatment, prevention or reduction of effects of neurodegeneration, free radical toxicity, hypoxia, and hyperglycemia.
Use as dietary supplements, functional foods, nutraceuticals, foods, beverages, drinks, medicaments, and compositions for rehydration.
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