Enantiomerically Enriched Hydroxybutyrate Ester Precursor

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Solution Overview

Problem

Direct administration of (R)-3-hydroxybutyrate or acetoacetate can cause acidosis and sodium overload, making it impractical and dangerous for elevating ketone body levels, while existing derivatives are unpalatable and difficult to administer orally.

Innovation Solution

Enantiomerically enriched 3-hydroxybutyl 3-hydroxybutyrate, specifically (3R,3R') enantiomer, is used as a precursor to (3R)-hydroxybutyrate, providing a palatable and effective means to elevate ketone body levels through oral administration, with a favorable pharmacokinetic profile.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If direct administration of (R)-3-hydroxybutyrate or acetoacetate is used to elevate ketone body levels, then the desired therapeutic effect is achieved, but acidosis and sodium overload occur making it dangerous and impractical

Engineering Contradiction:
Improvesafety of administrationVSAvoidacidosis and sodium overload
Core Design Contradiction:
ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent uses esters of (R)-3-hydroxybutyrate as intermediary compounds that serve as precursors to ketone bodies. These esters can be administered orally and are metabolized in the body to release ketone bodies, thereby elevating their blood levels without causing the harmful effects of direct acid administration. The ester serves as a safe mediator that delivers the active substance indirectly.

Inventive Principle:
Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the chemical form of (R)-3-hydroxybutyrate from its free acid form to ester form, altering its pharmacological properties. This parameter change allows the compound to be administered orally without causing acidosis, while still achieving the desired elevation of ketone body levels after metabolism in the body.

Inventive Principle:
Principle #35Parameter changes

2Reliability

If sodium salt of hydroxybutyrate is administered to achieve therapeutic levels, then ketone body elevation is achieved, but sodium overload occurs making it unsuitable

Engineering Contradiction:
Improvesafety of administrationVSAvoidsodium content
Core Design Contradiction:
ReliabilityVSQuantity of substance

Solution Approach 1:

The patent employs ester compounds as intermediaries that do not contain high levels of sodium. These esters are metabolized to release ketone bodies without introducing excessive sodium into the system, thus avoiding sodium overload while achieving the desired therapeutic effect.

Inventive Principle:
Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the chemical formulation from sodium salt to ester form, fundamentally altering the composition. This parameter change eliminates the sodium overload issue while preserving the ability to elevate ketone body levels through metabolic conversion.

Inventive Principle:
Principle #35Parameter changes

3Reliability

If existing derivatives of hydroxybutyrate are used to elevate ketone bodies, then the desired effect is achieved, but they are unpalatable and difficult to administer orally

Engineering Contradiction:
Improveeffectiveness in elevating ketone bodiesVSAvoidoral administrability and palatability
Core Design Contradiction:
ReliabilityVSEase of operation

Solution Approach 1:

The patent optimizes the chemical structure by selecting specific ester derivatives with favorable taste properties and bioavailability. This parameter change in the molecular structure makes the compound palatable and suitable for oral administration, resolving the issue of poor acceptability while maintaining effectiveness.

Inventive Principle:
Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The compound effectively raises blood levels of (3R)-hydroxybutyrate, promoting rapid and sustained effects, improving physical performance, weight management, and cognitive function, while being well-tolerated and easily ingested.

Implementation Method 1

3-hydroxybutyl 3-hydroxybutyrate enantiomerically enriched with respect to (3R)-hydroxybutyl (3R)-hydroxybutyrate

Methodology Applied
Scientific EffectHydrolysis: Hydrolysis

Data Source

PatentEP3296284B1Non-therapeutical use of hydroxybutyrate ester
Publication Date: 2021.12.01 OXFORD UNIVERSITY INNOVATION LTD
  • EP3296284B1 patent drawingFigure 1
  • EP3296284B1 patent drawingFigure 2
  • EP3296284B1 patent drawingFigure 3

AI summary

A compound which is 3-hydroxybutyl 3-hydroxybutyrate enantiomerically enriched with respect to (3?)»hydroxybutyl (3i?)-hydroxybutyrate of formula (I): is an effective and palatable precursor to the ketone body (3?)-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, neuro degeneration, free radical toxicity, hypoxic conditions or hyperglycaemia.